Device and implantation system for electrical stimulation of biological systems

ABSTRACT

The present specification discloses devices and methodologies for the treatment of transient lower esophageal sphincter relaxations (tLESRs). Individuals with tLESRs may be treated by implanting a stimulation device within the patient&#39;s lower esophageal sphincter and applying electrical stimulation to the patient&#39;s lower esophageal sphincter, in accordance with certain predefined protocols. The presently disclosed devices have a simplified design because they do not require sensing systems capable of sensing when a person is engaged in a wet swallow and have improved energy storage requirements.

CROSS REFERENCE

This application relies on U.S. Patent Provisional Nos. 61/310,755,filed on Mar. 5, 2010, 61/318,843, filed on Mar. 30, 2010, 61/328,702,filed on Apr. 28, 2010, 61/371,146, filed on Aug. 5, 2010, 61/384,105,filed on Sep. 17, 2010, 61/414,378, filed on Nov. 16, 2010, 61/422,967,filed on Dec. 14, 2010, and 61/444,849, filed on Feb. 21, 2011, forpriority. Each of the above applications are hereby incorporated byreference in their entireties.

FIELD OF THE INVENTION

This invention relates generally to a method and apparatus forelectrical stimulation of the biological systems. More particularly,this invention relates to a method and apparatus for treating transientlower esophageal sphincter relaxation (tLESR) by electricallystimulating a portion of the gastrointestinal system.

BACKGROUND OF THE INVENTION

In normal individuals, brief lower esophageal sphincter (LES) relaxationaccompanies peristalsis. Patients with transient lower esophagealsphincter relaxation (tLESR) experience LES relaxation at inappropriatetimes and independent of a swallow, such as after peristalsis, withfailed peristalsis, or spontaneously, lasting for up to 45 seconds. Forexample, tLESR may occur in the absence of a swallow and with noapparent triggering activity in the esophageal body. Spontaneously, LESpressure collapses, thereby enabling an episode of acid reflux, beforereturning to baseline. In cases where tLESR occurs after peristalsis, aperson may swallow during which the LES relaxes and contracts insequence with the peristaltic wave. However, the LES fails to completelyreturn to baseline pressure and, instead, relaxes again, thereby causingan episode of acid reflux. For failed peristalsis, the LES relaxes inthe absence of an expected bolus, again resulting in an episode of acidreflux.

While the typical acid load in a gastro-esophageal reflux disease (GERD)patient is greater than in a tLESR patient, tLESR is a common problemand expensive to manage in both primary and secondary care settings.This condition results from exposure of esophageal mucosa to gastricacid and bile as the gastro-duodenal content refluxes from the stomachinto the esophagus. The acid and bile damages the esophageal mucosaresulting in heartburn, ulcers, bleeding, and scarring, and long termcomplications such as Barrett's esophagus (pre-cancerous esophageallining) and adeno-cancer of the esophagus. Diagnostically, tLESR is anabrupt fall in LES pressure to a level of intragastric pressure that isnot triggered by swallowing and is manifested by a distinctive patternof mylohyoid or pharyngeal muscle contraction. Accepted criteria fordiagnosing a person with tLESR include (1) an absence of a pharyngealswallow signal for 4 seconds before to 2 seconds after the onset of LESrelaxation, or a mylohyoid electromyogram complex for 3 seconds beforethe onset of LES relaxation; (2) LES pressure fall of 1 mmHg/sec; (3) atime from the onset to complete relaxation of less than or equal to 10seconds; and (4) a nadir pressure of less than or equal to 2 mmHg. LESrelaxations where the LES pressure drops to 2 mmHg and has a duration ofgreater than 10 seconds can also be classified as tLESRs except thoseLES relaxations associated with multiple rapid swallows.

Lifestyle advice and antacid therapy are advocated as first linetreatment for the disease. The most commonly employed pharmacologicaltreatment is the use of H2 receptor antagonists (H2RAs) or proton-pumpinhibitors (PPIs) for acid suppression. Since reflux usually relapsesonce drug therapy is discontinued, most patients with the disease,therefore, need long-term drug therapy. However, daily use of PPIs orH2RAs is not universally effective in the relief of tLESR symptoms or asmaintenance therapy. Additionally, not all patients are comfortable withthe concept of having to take daily or intermittent medication for therest of their lives and many are interested in nonpharmacologicaloptions for managing their reflux disease.

Therefore, there is still a need for a safe and effective method oftreatment that can help alleviate symptoms of tLESR in the long term,without adversely affecting the quality of life of the patients. Inparticular, there is a need for simple, efficient tLESR device andtreatment methods that do not inhibit a patient from swallowing and donot rely on an instantaneous response from the patient's LES to avoidepisodes of tLESR. There is a need for treatment protocols and deviceswhich are programmed to implement such protocols, which can be easilyprogrammed and do not require complex physiologic sensing mechanisms inorder to operate effectively and safely. Moreover, there is not only aneed for better devices in stimulation based therapies, but there isalso a need for a safe and minimally invasive method and system thatenables easy and expeditious deployment of such devices at any desiredlocation in the body.

It is further desirable to have a system for the treatment of tLESRwhich includes a stimulator and an optional sensor adapted to be placedin a patient's LES tissue.

It is further desirable to have a system for the treatment of tLESRwhich includes an active implantable medical device (AIMD) and temporarysensor adapted to be placed in a patient's GI lumen where the sensorsare designed to naturally dissolve or pass out through the lumen and theAIMD is adapted to dynamically acquire, process, measure the quality of,and use sensed data only when the sensor is present.

It is further desirable to have a system for the temporary treatment oftLESR which includes an AIMD, which is adapted to be placed in apatient's GI lumen, designed to naturally dissolve or pass out throughthe lumen, and is adapted to deliver electrical stimulation to tissue ator in the vicinity of the LES. Such temporary stimulation scheme canadditionally be used for pre-screening of patients likely to benefitfrom permanent stimulation.

It would further be desirable for the stimulator to use periodic oroccasional sensing data to improve the treatment of tLESR by dynamicallydetecting when a sensor is present, determining when a sensor istransmitting, or capable of transmitting, data, and processing thesensed data using an application having a special mode whichopportunistically uses the sensed data to change stimulation parameters.

It is also desirable to automate the setting or calibration of some orall device parameters in order to reduce the need for medical follow-upvisits, reduce burdens on healthcare providers and patients, decreasethe rate of programming mistakes, and improve outcomes, therebyimproving the treatment of tLESR.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a system forincreasing pressure of a patient's lower esophageal sphincter (LES),comprising: at least one electrode contacting the LES; a waveformgenerator coupled to the electrodes; and a controller configured toelectrically stimulate the LES to increase the pressure of the LES, andmaintain an average pressure of the LES above a pressure level whichreduces at least one of a frequency of occurrence or an intensity oftransient lower esophageal sphincter relaxation (tLESR) symptoms in thepatient both during and after stimulation by controlling the waveformgenerator to repeatedly: a) generate and apply an electrical pulse trainto the LES through the electrodes for a stimulation period, and b)terminate the electrical pulse train for a rest period.

In one embodiment, the maintained average pressure does not inducedysphagia in the patient and allows the patient to swallow a bolusduring both the stimulation period and rest period.

In one embodiment, the controller is configured to determine parametersof the electrical pulse train that maintain the average pressure of theLES above the pressure level during the rest period.

In one embodiment, the controller is configured to control the waveformgenerator to stimulate the LES based on a predetermined trigger of atleast one of time of day and supine of the patient.

In one embodiment, the controller is configured to adjust a length ofthe stimulation period and a length of the rest period to maintain theaverage pressure of the LES above the pressure level.

In one embodiment, the system includes a sensor coupled to thecontroller for sensing physiological data of the patient, the sensorsensing at least one of pH level at the LES and pressure of the LES,wherein the controller is configured to control the waveform generatorbased on the sensed physiological data.

In one embodiment, the controller and the waveform generator areenclosed in a common housing and implanted in the patient.

In one embodiment, the system includes an external programming devicefor configuring the controller to adjust at least one of the energy perstimulation period, duration of the stimulation period, frequency of thestimulation period, and a number of stimulation periods per day based onat least one of the frequency of occurrence or the intensity of tLESRsymptoms in the patient.

In one embodiment, the system includes a disposable battery coupled tothe waveform generator and the controller for powering the waveformgenerator and the controller.

In one embodiment, the controller is configured to control the waveformgenerator to set a pulse width of the electrical pulse train in a rangefrom 1 μs to 1 second.

In one embodiment, the controller is configured to control the waveformgenerator to set a frequency of the electrical pulse train in a rangefrom about 1 Hz to about 100 Hz.

In one embodiment, the controller is configured to control the waveformgenerator to set a current of pulses in the electrical pulse train in arange from 1 μAmp to 50 mAmps.

In one embodiment, the system includes a sensor coupled to thecontroller for sensing physiological data of a patient; and a memorycoupled to the controller for storing the sensed data of the patient,wherein the controller is configured to control the waveform generatorto adjust parameters of the electrical pulse train applied to the LESbased on an analysis of the stored data.

In one embodiment, the system includes at least one of an accelerometerand inclinometer coupled to the controller for sensing posture data ofthe patient, wherein the controller is configured to control thewaveform generator to adjust parameters of the electrical pulse trainapplied to the LES based on an analysis of the posture data.

In one embodiment, the system includes an antenna coupled to thecontroller for wirelessly receiving instructions for instructing thecontroller to adjust parameters of the electrical pulse train applied tothe LES, wherein the instructions are set by at least one of the patientand a trained professional.

In one embodiment, the controller is configured to perform a diagnostictest on the patient by controlling the waveform generator to adjust anamount of electrical energy stimulating the LES over a treatment periodbased on at least one of the frequency of occurrence or the intensity oftLESR symptoms in the patient.

In one embodiment, a system is included for increasing pressure of apatient's lower esophageal sphincter (LES), comprising: at least oneelectrode contacting the LES; a waveform generator coupled to theelectrodes; and a controller configured to control the waveformgenerator to generate and apply an electrical pulse train to the LESthrough the electrodes during a stimulation period to produce anincrease in the pressure of the LES during a rest period aftertermination of the electrical pulse train, the pressure of the LESdetermined to increase during the rest period above a pressure levelwhich reduces at least one of a frequency of occurrence or an intensityof tLESR symptoms in the patient.

In one embodiment, prior to stimulation, the controller is configuredwith a length of the stimulation period and an electrical current of thepulse train that increases the LES pressure above the pressure levelduring the rest period.

In one embodiment, prior to stimulation, the controller is configured todetermine a length of the rest period that allows the pressure of theLES to increase above the pressure level and does not allow the pressureof the LES to decrease below the pressure level.

In one embodiment, the controller is configured with parameters of theelectrical pulse train that produce a first increase in LES pressureduring the stimulation period, and a second increase in LES pressureduring the rest period.

In one embodiment, the controller is configured to determine parametersof the electrical pulse train that produce an increase in the LESpressure at a first rate during the stimulation period and at a secondrate during the rest period.

In one embodiment, includes is a system for increasing pressure of apatient's lower esophageal sphincter (LES), comprising: at least oneelectrode contacting the LES;

a waveform generator coupled to the electrodes; and a controllerconfigured to control the waveform generator to generate and apply anelectrical pulse train to the LES through the electrodes to increase thepressure of the LES, and maintain an average pressure of the LES above apressure level which reduces at least one of a frequency of occurrenceor an intensity of tLESR symptoms in the patient while allowing thepatient to swallow during electrical stimulation.

In one embodiment, the bolus has a volume of greater than 1 cubiccentimeter (cc).

In one embodiment, the controller is configured to control the waveformgenerator so that the increased pressure level of the LES is below apressure level that prevents the patient from swallowing a bolus.

In one embodiment, the controller is configured to control the waveformgenerator so that the increased pressure level of the LES is below apressure level that restricts the opening capacity of patient's LES whenswallowing a bolus.

In one embodiment, the controller is configured to control the waveformgenerator so that the electrical stimulation does not inhibit apatient's esophageal motility.

In one embodiment, included is a system for increasing pressure of apatient lower esophageal sphincter (LES), comprising: at least oneelectrode contacting the LES; a waveform generator coupled to theelectrodes; a battery powering the waveform generator; and a controllerconfigured to control the waveform generator to generate and apply anelectrical pulse train to the LES through the electrodes to increase thepressure of the LES, the electrical pulse train being controlled by thecontroller so that an amount of electrical energy consumed from thebattery when stimulating the LES is an energy amount that maintains anaverage pressure of the LES above a pressure level which reduces atleast one of a frequency of occurrence or an intensity of tLESR symptomsin the patient while maintaining at least a minimum charge on thebattery to electrically power the waveform generator for a predeterminedtime period.

In one embodiment, the controller is configured to determine astimulation time for stimulating the LES to reduce at least one of thefrequency of occurrence or the intensity of tLESR symptoms in thepatient, and electrically power the waveform generator for thepredetermined time period.

In one embodiment, the controller is configured to determine at leastone of a pulse width, electrical current, frequency and energy of theelectrical pulse train to reduce at least one of the frequency ofoccurrence or the intensity of tLESR symptoms in the patient, andelectrically power the waveform generator for the predetermined timeperiod.

In one embodiment, the controller is configured to consume between 30nano-amp hours and 3 micro-amp-hours of energy during a stimulationperiod to reduce the tLESR symptoms in the patient for at least onehour, and does not consume more than 3 micro-amp hours of energy perstimulation period.

In one embodiment, the controller is configured to cumulatively consumebetween 300 nano-amp hours and 30 micro-amp-hours of energy over aplurality of stimulation periods to reduce the tLESR symptoms in thepatient for at least 24 hours, and does not consume more than 30micro-amp hours of energy per day.

In one embodiment, the system includes a macrostimulator comprising atleast one electrode, an energy source, and a pulse generator inelectrical communication with the at least one electrode and energysource, wherein said pulse generator is programmed, adapted to beimplanted in a patient and configured to stimulate the patient's LES.

In one embodiment, the system includes a macrostimulator implanted in apatient comprising at least one electrode, an energy source, and a pulsegenerator in electrical communication with the at least one electrodeand energy source, wherein said pulse generator is configured tostimulate the patient's LES and wherein electrical stimulation isinitiated, terminated or otherwise modified based upon sensed data.

In one embodiment, the system includes a macrostimulator comprising atleast one electrode, an energy source, and a pulse generator inelectrical communication with the at least one electrode and energysource, wherein said pulse generator is programmed to stimulate thepatient's LES and wherein electrical stimulation is initiated,terminated or otherwise modified based upon sensed data.

In one embodiment, the system includes a macrostimulator implanted in apatient comprising at least one electrode, an energy source, and a pulsegenerator in electrical communication with the at least one electrodeand energy source, wherein said pulse generator is adapted to stimulatethe patient's LES, and wherein electrical stimulation is initiated,terminated, or otherwise modified based upon sensed data.

In one embodiment, the electrical stimulation by the macrostimulator isinitiated or terminated based upon sensed data and wherein the senseddata is at least one of LES pressure, esophageal pH, inclinometer data,temperature, or accelerometer data.

In one embodiment, the macrostimulator comprises at least one electrode,an energy source, and a pulse generator in electrical communication withthe at least one electrode and energy source, wherein said pulsegenerator is configured to stimulate the patient's LES, and whereinelectrical stimulation is initiated or terminated based upon sensed dataand wherein the sensed data is at least one of LES pressure, esophagealpH, inclinometer data, temperature, or accelerometer data.

In one embodiment, the macrostimulator is implanted in a patientcomprises at least one electrode, an energy source, and a pulsegenerator in electrical communication with the at least one electrodeand energy source, wherein said pulse generator is programmed, adaptedto, or configured to stimulate the patient's LES, and wherein electricalstimulation is initiated or terminated based upon sensed data andwherein the sensed data is at least one of LES pressure, esophageal pH,inclinometer data, temperature, or accelerometer data.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a pulse generator in electricalcommunication with at least one electrode; (b) an energy storagecomponent, wherein said pulse generator generates a pulse stream inaccordance with a preset period and wherein said system does not includea sensor for sensing a physiological state of a patient.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a pulse generator in electricalcommunication with at least one electrode; (b) an energy storagecomponent, wherein said pulse generator generates a pulse stream inaccordance with a preset period and wherein said preset period is notdependent upon a physiological state of a patient.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a pulse generator in electricalcommunication with at least one electrode; (b) an energy storagecomponent, wherein said pulse generator generates a pulse stream inaccordance with a preset period and wherein said preset period is notlengthened or shortened based upon a feeding state of a patient.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a pulse generator in electricalcommunication with at least one electrode; (b) an energy storagecomponent, wherein said pulse generator generates a pulse stream for anon period and wherein said on period is between 1 second and 24 hoursand wherein said on period is not lengthened or shortened based upon afeeding state of a patient.

In one embodiment, included is an implantable system for treating agastrointestinal condition of a patient, comprising: (a) a passivestimulator for receiving energy from a source; (b) a pulse generator incommunication with said passive stimulator wherein said pulse generatorgenerates a pulse in accordance with a preset period and wherein saidsystem does not include a sensor for sensing a physiological state of apatient.

In one embodiment, included is an implantable system for treating agastrointestinal condition of a patient, comprising: (a) a passivestimulator for receiving energy from a source; (b) a pulse generator inelectrical communication with said passive stimulator wherein said pulsegenerator generates a pulse in accordance with a preset period andwherein said system does not include an implantable energy storagecomponent.

In one embodiment, included is an implantable system for treating agastrointestinal condition of a patient, comprising: (a) a passivestimulator for receiving energy from a source; (b) a pulse generator inelectrical communication with said passive stimulator wherein said pulsegenerator generates a pulse in accordance with a preset period andwherein said preset period is not dependent upon a physiological stateof a patient.

In one embodiment, included is an implantable system for treating agastrointestinal condition of a patient, comprising: (a) a passivestimulator for receiving energy from a source; (b) a pulse generator inelectrical communication with said passive stimulator wherein said pulsegenerator generates a pulse in accordance with a preset period andwherein said preset period is not lengthened or shortened based upon afeeding state of a patient.

In one embodiment, included is an implantable system for treating agastrointestinal condition of a patient, comprising: (a) a passivestimulator for receiving energy from a source; (b) a pulse generator inelectrical communication with said passive stimulator wherein said pulsegenerator generates a pulse in accordance with an on period and whereinsaid on period is between 1 second and 24 hours and wherein said onperiod is not lengthened or shortened based upon a feeding state of apatient.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a stimulator adapted to beimplanted proximate to or within a LES of the patient; (b) an energyreceiver in electrical communication with the stimulator; and (c) anenergy transmitter, wherein said energy transmitter is adapted to beexternal to the patient's body and configured to wirelessly transmitelectrical energy to said energy receiver.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a stimulator adapted to beimplanted proximate to or within a LES of the patient; (b) an energyreceiver in electrical communication with the stimulator; and (c) anenergy transmitter, wherein said energy transmitter is adapted to beexternal to the patient's body and configured to wirelessly transmitelectrical energy to said energy receiver and wherein said energytransmitter transmits energy in accordance with a preset period andwherein said system does not include a sensor for sensing aphysiological state of a patient.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a stimulator adapted to beimplanted proximate to or within a LES of the patient; (b) an energyreceiver in electrical communication with the stimulator; and (c) anenergy transmitter, wherein said energy transmitter is adapted to beexternal to the patient's body and configured to wirelessly transmitelectrical energy to said energy receiver and wherein said energytransmitter transmits energy in accordance with a preset period andwherein said preset period is not dependent upon a physiological stateof a patient.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a stimulator adapted to beimplanted proximate to or within a LES of the patient; (b) an energyreceiver in electrical communication with the stimulator; and (c) anenergy transmitter, wherein said energy transmitter is adapted to beexternal to the patient's body and configured to wirelessly transmitelectrical energy to said energy receiver and wherein said energytransmitter transmits energy in accordance with a preset period andwherein said preset period is not lengthened or shortened based upon afeeding state of a patient.

In one embodiment, included is a system for treating a gastrointestinalcondition of a patient, comprising: (a) a stimulator adapted to beimplanted proximate to or within a LES of the patient; (b) an energyreceiver in electrical communication with the stimulator; and (c) anenergy transmitter, wherein said energy transmitter is adapted to beexternal to the patient's body and configured to wirelessly transmitelectrical energy to said energy receiver and wherein said energytransmitter transmits energy in accordance with an on period and whereinsaid on period is between 1 second and 24 hours and wherein said onperiod is not lengthened or shortened based upon a feeding state of apatient.

In one embodiment, the energy delivered to the stimulator has a pulsewidth in a range of 1 μsec to 1 second.

In one embodiment, the energy delivered to the stimulator has a pulsefrequency in a range of 1 Hz to 100 Hz.

In one embodiment, the energy delivered to the stimulator has a pulseamplitude in a range of 1 μAmp to 50 mAmp.

In one embodiment, the energy delivered to the stimulator has a pulseamplitude in a range of 1 μAmp to 50 mAmp.

In one embodiment, after cessation of stimulation, the LES has a normalphysiological behavior.

In one embodiment, included is a system for stimulating an anatomicalstructure within a patient, comprising: (a) a stimulator adapted to beimplanted into the patient; and (b) a sensor adapted to be temporarilypositioned within a lumen of the patient separate from said stimulator,wherein said sensor is configured to sense a physiological parameter ofthe patient and communicate data indicative of said physiologicalparameter to the stimulator and wherein said stimulator modifies atleast one stimulation parameter based upon said data.

In one embodiment, included is a system for collecting data from withina patient and transmitting the data outside the patient's body,comprising: (a) a logging device adapted to be implanted into thepatient, wherein the logging device comprises a memory adapted to storea plurality of data; and (b) a sensor adapted to be temporarilyimplanted into a lumen of the patient separate from said logging device,wherein said sensor is configured to sense a physiological parameter ofthe patient and communicate said sensed data to the logging device andwherein said logging device is capable of storing the sensed data andwirelessly transmitting sensed data to a receiver located outside thebody.

In one embodiment, the stimulator comprises a structure that housesstimulating circuitry, a receiver to receive said data from the sensor,and a control unit that analyzes the received data and adjusts said atleast one stimulation parameter.

In one embodiment, the stimulating circuitry comprises a power sourceand means for delivering stimulation.

In one embodiment, the means for delivering stimulation includes atleast one of an electrical lead or electrical contact.

In one embodiment, the sensor is adapted to be temporarily located inthe body for a duration less than one month

In one embodiment, the sensor is a pH capsule.

In one embodiment, the sensor is adapted to measure physiological pH andtransmit pH data from within a lumen of the patient's esophagus.

In one embodiment, the sensor comprises a pH sensor located within anasogastric tube.

In one embodiment, the sensor transmits pH data to the stimulator viauni-directional or bi-directional communications.

In one embodiment, the stimulator comprises a controller that is adaptedto execute a plurality of programmatic instructions to adjust said atleast one stimulation parameter based upon said data, wherein said datais pH data.

In one embodiment, the pH data is continuously streamed to thestimulator from a pH capsule.

In one embodiment, the controller adjusts one or more stimulationparameters to increase a stimulation dose to the patient if, within apredefined period, the pH data is less than a first threshold value fora percentage of time higher than a second threshold value.

In one embodiment, the first threshold is 4.

In one embodiment, the second threshold is 5 percent.

In one embodiment, the stimulation parameters include at least one ofnumber of stimulation events or size of each stimulation event.

In one embodiment, the at least one of said stimulation parameters isbounded by a maximum value.

In one embodiment, the at least one of said stimulation parameters isbounded by a minimum value.

In one embodiment, the controller adjusts one or more stimulationparameters to decrease a stimulation dose to the patient if, within apredefined period, the pH data is less than a first threshold value fora percentage of time less than a second threshold value.

In one embodiment, the first threshold is 4.

In one embodiment, the second threshold is 1 percent.

In one embodiment, the stimulation parameters include at least one ofnumber of stimulation events or size of each stimulation event.

In one embodiment, the at least one of said stimulation parameters isbounded by a maximum value.

In one embodiment, the at least one of said stimulation parameters isbounded by a minimum value.

In one embodiment, the stimulator comprises a controller that is adaptedto execute a plurality of programmatic instructions to adjust said atleast one stimulation parameter based upon said data, wherein said datacomprises at least one of pH data, accelerometer data, inclinometerdata, impedance data or a combination thereof.

In one embodiment, the data is transmitted from the stimulator to adevice which is located external to the patient.

In one embodiment, the transmission occurs automatically when thepatient and external device are within a predefined proximity.

In one embodiment, the transmission is enabled when the patient andexternal device are within a predefined proximity and only occurs whenexpressly authorized by the patient.

In one embodiment, the external device is adapted to receive dataindicative of stimulation parameters from a second external device andcommunicate said data indicative of stimulation parameters to thestimulator within the patient.

In one embodiment, the stimulator comprises a controller that is adaptedto monitor a status of said sensor.

In one embodiment, if said sensor fails to respond to communicateattempts from said controller or fails a diagnostic test, the controllergenerates a signal indicative of a sensor failure state.

In one embodiment, if said controller receives data indicating thesensor has migrated from a desired position to an undesired position,the controller generates a signal indicative of a sensor failure state.

In one embodiment, the data indicating the sensor has migrated from adesired position to an undesired position includes pH less than athreshold value for greater than a predefined a period of time.

In one embodiment, the stimulator comprises a structure that housesstimulating circuitry, a receiving antenna to receive said data from thesensor, and a control unit that analyzes the received data and adjustssaid at least one stimulation parameter.

In one embodiment, the receiving antenna can be additionally used toenable energy transfer to said stimulator.

In one embodiment, the said sensor comprises a local energy source andis adapted to transfer energy from said sensor to the stimulator.

In one embodiment, the sensor is a pH capsule or is anchored in anasogastric tube.

In one embodiment, includes is a method of treating a patient with tLESRsymptoms, wherein said patient has a lower esophageal sphincter (LES)and wherein said LES has a pressure, the method comprising: maintainingan average pressure of the LES above a pressure level which reduces atleast one of a frequency of occurrence or an intensity of the tLESRsymptoms both during and after stimulation by applying an electricalpulse train to the LES through electrodes for a stimulation period toincrease the pressure of the LES above the pressure level, andterminating the electrical pulse train for a rest period.

In one embodiment, the LES is repeatedly stimulated to maintain theaverage pressure of the LES in a pressure range which is above a firstpressure level to at least one of the frequency of occurrence or theintensity of the tLESR symptoms in the patient and below a secondpressure level to allow the patient to swallow during both thestimulation period and rest period.

In one embodiment, a controller determines parameters of the electricalpulse train that maintain the average pressure of the LES above thepressure level during the rest period.

In one embodiment, the controller controls a waveform generator tostimulate the LES when the pressure of the LES decreases to a thirdpressure level during the rest period.

In one embodiment, the controller adjusts a length of the stimulationperiod and a length of the rest period to maintain the average pressureof the LES above the pressure level.

In one embodiment, the controller is configured to control the waveformgenerator to set a pulse width of the electrical pulse train in a rangefrom about 1 μs to about 1 second.

In one embodiment, the controller is configured to control the waveformgenerator to set a frequency of the electrical pulse train in a rangefrom about 1 Hz to about 100 Hz.

In one embodiment, the controller is configured to control the waveformgenerator to set a current of pulses in the electrical pulse train in arange from about 1 μAmp to about 50 mAmps.

In one embodiment, the controller is configured to perform a diagnostictest on the patient by controlling the waveform generator to varyparameters of the electrical pulse train to determine a pressureresponse of the LES based on different electrical stimulation.

In one embodiment, achieving said pressure level occurs after a minimumperiod selected from the group consisting of at least 5 minutes, 10minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 12 hours, 24hours, or any time increment therein.

In one embodiment, the said electrical stimulation is initiated prior toa predetermined time; said predetermined time is associated with antLESR triggering event; and said initiation occurs prior to saidpredetermined time by a minimum period selected from the groupconsisting of at least 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1hour, 2 hours, 3 hours, 12 hours, 24 hours, or any time incrementtherein.

In one embodiment, programming said stimulation device, wherein saidprogramming is dependent upon a plurality of stimulation parameters thatdetermine the application of electrical stimulation to the patient LES,and wherein said stimulation parameters are selected, at least in part,to treat tLESR without inhibiting patient swallowing.

In one embodiment, the electrical stimulation is applied to the patientLES while the patient swallows, during periods of esophageal motility,or during esophageal peristalsis.

In one embodiment, the electrical stimulation is applied to the patientLES in accordance with a preset period and wherein said preset period isnot dependent upon a physiological state of a patient.

In one embodiment, the electrical stimulation is applied to the patientLES in accordance with a preset period and wherein said preset period isnot dependent upon the patient swallowing, esophageal motility,esophageal peristalsis, or being in a feeding state.

In one embodiment, the electrical stimulation is applied to the patientLES that is not dependent upon a physiological state of the patient.

In one embodiment, electrical stimulation is applied to the patient LESthat is not dependent upon a sensed physiological state of the patient.

In one embodiment, electrical stimulation is applied to the patient LESthat is not dependent upon the patient swallowing, esophageal motility,esophageal peristalsis, or being in a feeding state.

In one embodiment, sufficient electrical stimulation is applied to thepatient LES to increase said pressure but not to inhibit patientswallowing, esophageal motility, or esophageal peristalsis.

In one embodiment, electrical stimulation is applied to the patient LEScausing an increase in said pressure of at least 5% only after anelapsed period of time of at least one minute.

In one embodiment, the electrical stimulation normalizes loweresophageal function, normalizes LES pressure, or increases LES pressureto a normal physiological range only after an elapsed period of time ofat least one minute.

In one embodiment, the stimulation causes a non-instantaneous or delayedincrease in said pressure.

In one embodiment, the electrical stimulation causes a delayed increasein said pressure and wherein said delayed increase in the pressurenormalizes LES function, normalizes LES pressure, increases LES pressureto a normal physiological range, or increases LES pressure by at least3%.

In one embodiment, the electrical stimulation causes an increase in saidpressure after said electrical stimulation is terminated.

In one embodiment, the electrical stimulation has a first level, whereinsaid stimulation causes an increase in said pressure after saidelectrical stimulation is decreased from said first level.

In one embodiment, the electrical stimulation is applied in accordancewith at least one on period, wherein said on period is between 1 secondand 24 hours and is not triggered by, substantially concurrent to, orsubstantially simultaneous with an incidence of tLESR, and at least oneoff period, wherein said off period is greater than 10 seconds.

In one embodiment, the electrical stimulation is applied having acurrent from a single electrode pair ranging from about 1 mAmp to about8 mAmp.

In one embodiment, the electrical stimulation has a pulse durationwithin a range of 5 μsec to 1 second.

In one embodiment, the electrical stimulation has a pulse duration ofapproximately 1 msec.

In one embodiment, the electrical stimulation has a pulse duration ofapproximately 200 μsec.

In one embodiment, the device incorporates an accelerometer orinclinometer to measure patient positional activity; and applyingelectrical stimulation based upon one or more of the followingparameters as measured by said accelerometer or inclinometer: time spentin the supine position or level of inclination.

In one embodiment, includes is a method of treating a patient with tLESRsymptoms, the method comprising: (a) implanting a stimulation device inthe patient to contact the patient LES, (b) applying electricalstimulation to the patient LES, and (b) maintaining an average pressureof the LES above a pressure level both during and after electricalstimulation for a stimulation period to increase the pressure of the LESabove the pressure level, and terminating the electrical stimulation fora rest period.

In one embodiment, achieving said pressure level occurs after a minimumperiod selected from the group consisting of at least 5 minutes, 10minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 12 hours, 24hours, or any time increment therein.

In one embodiment, the electrical stimulation is initiated prior to apredetermined time; said predetermined time is associated with an tLESRtriggering event; and said initiation occurs prior to said predeterminedtime by a minimum period selected from the group consisting of at least5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours,12 hours, 24 hours, or any time increment therein.

In one embodiment, including programming said stimulation device,wherein said programming is dependent upon a plurality of stimulationparameters that determine the application of electrical stimulation tothe patient LES, and wherein said stimulation parameters are selected,at least in part, to treat tLESR symptoms without inhibiting patientswallowing.

In one embodiment, electrical stimulation is applied to the patient LESwhile the patient swallows, during periods of esophageal motility, orduring esophageal peristalsis.

In one embodiment, electrical stimulation is applied to the patient LESin accordance with a preset period and wherein said preset period is notdependent upon a physiological state of a patient.

In one embodiment, electrical stimulation is applied to the patient LESin accordance with a preset period and wherein said preset period is notdependent upon the patient swallowing, esophageal motility, esophagealperistalsis, or being in a feeding state.

In one embodiment, electrical stimulation is applied to the patient LESthat is not dependent upon a physiological state of the patient.

In one embodiment, electrical stimulation is applied to the patient LESthat is not dependent upon a sensed physiological state of the patient.

In one embodiment, electrical stimulation is applied to the patient LESthat is not dependent upon the patient swallowing, esophageal motility,esophageal peristalsis, or being in a feeding state.

In one embodiment, sufficient electrical stimulation is applied to thepatient LES to increase said pressure but not to inhibit patientswallowing, esophageal motility, or esophageal peristalsis.

In one embodiment, electrical stimulation is applied to the patient LEScausing an increase in said pressure of at least 5% only after anelapsed period of time of at least one minute.

In one embodiment, the electrical stimulation normalizes loweresophageal function, normalizes LES pressure, or increases LES pressureto a normal physiological range only after an elapsed period of time ofat least one minute.

In one embodiment, the stimulation causes a non-instantaneous or delayedincrease in said pressure.

In one embodiment, the electrical stimulation causes a delayed increasein said pressure and wherein said delayed increase in the pressurenormalizes LES function, normalizes LES pressure, increases LES pressureto a normal physiological range, or increases LES pressure by at least3%.

In one embodiment, the electrical stimulation causes an increase in saidpressure after said electrical stimulation is terminated.

In one embodiment, the electrical stimulation has a first level, whereinsaid stimulation causes an increase in said pressure after saidelectrical stimulation is decreased from said first level.

In one embodiment, the electrical stimulation is applied in accordancewith at least one on period, wherein said on period is between 1 secondand 24 hours and is not triggered by, substantially concurrent to, orsubstantially simultaneous with an incidence of tLESR, and at least oneoff period, wherein said off period is greater than 10 seconds.

In one embodiment, the electrical stimulation is applied having acurrent from a single electrode pair ranging from about 1 mAmp to about8 mAmp.

In one embodiment, the electrical stimulation has a pulse durationwithin a range of 5 μsec to 1 second.

In one embodiment, the electrical stimulation has a pulse duration ofapproximately 1 msec.

In one embodiment, the electrical stimulation has a pulse duration ofapproximately 200 μsec.

In one embodiment, the device incorporates an accelerometer orinclinometer to measure patient positional activity; and applyingelectrical stimulation based upon one or more of the followingparameters as measured by said accelerometer or inclinometer: time spentin the supine position or level of inclination.

In one embodiment, includes is a method of treating a patient with tLESRsymptoms, the method comprising: (a) implanting the stimulation devicein the patient to contact the patient LES; (b) applying electricalstimulation to the patient LES; (b) measuring one or more parametersselected from the group consisting of patient feed state including typeof feed; patient position; patient activity; patient reflux profile; LESpressure; LES electrical activity; LES mechanical activity gastricpressure; gastric electrical activity; gastric chemical activity;gastric temperature; gastric mechanical activity; patient intuition;vagal neural activity; and, splanchnic neural activity; (c) inputtingthe collected data into an algorithm; and (d) applying electricalstimulation based upon a summary score calculated by said algorithm tomaintain an average pressure of the LES above a pressure level bothduring and after electrical stimulation for a stimulation period toincrease the pressure of the LES above the pressure level, andterminating the electrical stimulation for a rest period.

In one embodiment, included is a method of programming a stimulatorwherein said stimulator is implanted proximate to a lower esophagealsphincter of a patient, comprising the steps of: (a) causing saidstimulator to stimulate the lower esophageal sphincter; (b) monitoring apressure level of said lower esophageal sphincter while said stimulatoris stimulating the lower esophageal sphincter; (c) recording a time whenthe pressure level of said lower esophageal sphincter exceeds a firstthreshold value; (d) terminating said stimulation when the pressurelevel of said lower esophageal sphincter exceeds a first pressure value;(e) monitoring the pressure level of said lower esophageal sphincterafter terminating said stimulation; (f) recording a time when thepressure level of said lower esophageal sphincter reaches a secondpressure value; and (g) programming the stimulator to operate for afixed, preset period of time.

In one embodiment, included is a method of programming a stimulatorwherein said stimulator is implanted proximate to a lower esophagealsphincter of a patient, comprising the steps of: (a) causing saidstimulator to stimulate the lower esophageal sphincter; (b) recording atime and an electrode impedance value when said stimulation is started;(c) monitoring a pressure level of said lower esophageal sphincter whilesaid stimulation is being applied; (d) recording a time when thepressure level of said lower esophageal sphincter exceeds a firstthreshold value; (e) recording an electrode impedance value when thepressure level of said lower esophageal sphincter exceeds the firstthreshold value; (f) terminating said energy input to said stimulatorwhen the pressure level of said lower esophageal sphincter exceeds afirst pressure value; (g) monitoring the pressure level of said loweresophageal sphincter after terminating said stimulation; (h) recording atime when the pressure level of said lower esophageal sphincter reachesa second pressure value; (i) recording an electrode impedance value whenthe pressure level of said lower esophageal sphincter reaches the secondpressure value;

In one embodiment, included is a method of programming a stimulatorwherein said stimulator is implanted proximate to a lower esophagealsphincter of a patient, comprising the steps of: (a) applying an energyinput to said stimulator to cause said stimulator to stimulate the loweresophageal sphincter; (b) recording a time and a electrode impedancevalue when said energy input is first applied to said stimulator; (c)monitoring a pressure level of said lower esophageal sphincter whilesaid energy input is being applied to said stimulator; (d) recording atime when the pressure level of said lower esophageal sphincter exceedsa first threshold value; (e) recording a electrode impedance value whenthe pressure level of said lower esophageal sphincter exceeds the firstthreshold value; (f) terminating said energy input to said stimulatorwhen the pressure level of said lower esophageal sphincter exceeds afirst pressure value; (g) monitoring the pressure level of said loweresophageal sphincter after terminating said energy input to saidstimulator; (h) recording a time when the pressure level of said loweresophageal sphincter reaches a second pressure value; (i) recording aelectrode impedance value when the pressure level of said loweresophageal sphincter reaches the second pressure value; (j) programmingthe stimulator to operate for a fixed, preset period of time.

In one embodiment, the fixed, preset period of time is between 1 minutesand 12 hours.

In one embodiment, the fixed, preset period of time is not dependent ona feeding state of the patient.

In one embodiment, the fixed, preset period of time is not dependent onwhether the patient is engaging in a swallow.

In one embodiment, the recording and monitoring steps are performedautomatically by a system in data communication with a manometrymeasurement system.

In one embodiment, the energy input has a pulse frequency ofapproximately 20 Hz, a pulse duration of approximately 200 μsec, and apulse amplitude in a range of 0.1 mAmp to 15 mAmp.

In one embodiment, the first pressure value is at least 20 mmHg.

In one embodiment, the second pressure value is at most 10 mmHg.

In one embodiment, the second pressure value is proportional to abaseline pressure level of the patient's lower esophageal sphincter.

These and other embodiments shall be discussed in greater detail belowand in relation to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects and advantages of the presently disclosedtreatment methodologies, devices, and systems will become more fullyapparent from the following detailed description when read inconjunction with the accompanying drawings with like reference numeralsindicating corresponding parts through-out, wherein:

FIG. 1 depicts the physiology of a normal swallow;

FIG. 2 depicts a wet swallow at baseline for a patient;

FIG. 3 depicts a wet swallow with stimulation;

FIG. 4 depicts one exemplary pressure profile, both during stimulationand post-stimulation;

FIG. 5 depicts another exemplary pressure profile, both duringstimulation and post-stimulation;

FIG. 6 depicts another exemplary pressure profile, both duringstimulation and post-stimulation;

FIG. 7 depicts yet another exemplary pressure profile, both duringstimulation and post-stimulation;

FIG. 8 is a schematic of modulated pulse trains;

FIG. 9 is an illustration of a timeline depicting a stimulation sessionfollowed by a supine refractory time period;

FIG. 10 is an illustration of a timeline depicting a stimulation sessiontriggered by supine stimulation mode followed by a supine cancel period;

FIG. 11 depicts one exemplary electrode configuration in the esophagusof a patient;

FIG. 12 depicts another exemplary electrode configuration in theesophagus of a patient;

FIG. 13 depicts another exemplary electrode configuration in theesophagus of a patient;

FIG. 14 is a cross-sectional illustration of the upper gastrointestinaltract showing a pH sensing capsule in the esophagus and a stimulatoradapted to be implanted within the tissue of the patient;

FIG. 15 is a flow sheet depicting a certain parameter setting method ofone embodiment of the present invention;

FIG. 16 is a first embodiment of a block diagram of certain modules ofthe present invention;

FIG. 17 is a second embodiment of a block diagram of certain modules ofthe present invention;

FIG. 18 is a third embodiment of a block diagram of certain modules ofthe present invention;

FIG. 19 is a fourth embodiment of a block diagram of certain modules ofthe present invention;

FIG. 20 is a fifth embodiment of a block diagram of certain modules ofthe present invention;

FIG. 21 is a sixth embodiment of a block diagram of certain modules ofthe present invention;

FIG. 22 is a seventh embodiment of a block diagram of certain modules ofthe present invention;

FIG. 23 is a eighth embodiment of a block diagram of certain modules ofthe present invention;

FIG. 24 is a graph relating pressure increases to baseline, stimulation,and post-stimulation periods;

FIG. 25 is a graph showing an improved LES pressure profile over time;

FIG. 26 is a graph showing a decrease in esophageal acid exposure overtime;

FIG. 27 is a graph showing a decrease in adverse symptoms over time; and

FIG. 28 is a graph showing an improved LES pressure profile over time.

FIG. 29 is a graph showing an improved LES pressure profile over time;and

FIG. 30 is a graph showing the pressure profile of three patients overtime.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed toward programmable implantableelectro-medical device for the treatment of transient lower esophagealsphincter relaxation (tLESR). The electro-medical device of the presentinvention employs stimulators, including macrostimulators ormicrostimulators, which can be implanted with minimal invasiveness inthe gastrointestinal system. Specifically, these devices can bebeneficial for deep implant locations for which there is a naturalorifice access providing closer proximity than from outside the body. Itshould further be appreciated that the present device is capable ofstimulating all smooth muscle, not limited to GI smooth muscles and thatthe present device can be used to deliver stimulation to the proximalstomach or area adjacent to the proximal stomach for treating variousdiseases that can be affected by gastric stimulation such as gastricmotility problems and diabetes. The present application furtherincorporates by reference U.S. Pat. No. 6,901,295, PCT/US08/56479, andU.S. patent application Ser. Nos. 12/030,222, 11/539,645, and 12/359,317in their entirety.

The systems and methods disclosed herein can be used to achieve aplurality of different therapeutic objectives: treatment of tLESR;normalizing a patient's LES function; treatment of hypotensive LES;increase resting or baseline LES pressure; treating a patient tonormalize esophageal pH, wherein said normalization is achieved when apatient has an esophageal pH value of less than 4 for a period of timeno greater than 5%, 10%, or 15% of a 24 hour period or some fractionthereof; treating a patient to normalize esophageal pH when in thesupine position, wherein said normalization is achieved when a patienthas an esophageal pH value of less than 4 for a period of time nogreater than 3% of a 24 hour period; treating a patient to preventdamage to the patient's lower esophageal sphincter caused by acidreflux; treatment of supine position induced tLESR; treatment ofactivity-induced tLESR; prevention of supine position induced tLESR;prevention of activity-induced tLESR; treating a patient to mitigatedamage to the patient's lower esophageal sphincter caused by acidreflux; treating a patient to stop progression of damage to thepatient's lower esophageal sphincter caused by acid reflux; treating apatient to minimize transient relaxations of the patient's loweresophageal sphincter; modifying or increasing LES pressure; modifying orincreasing esophageal body pressure; modifying or improving esophagealbody function; modifying or improving esophageal sensation induced bythe refluxate; modifying or improving the volume of refluxate; modifyingor improving the clearance of the refluxate; reducing incidents ofheartburn; modifying or improving esophageal acid exposure; increasinglower esophageal tone; detecting when a patient swallows; detecting whena patient is eating; treating a gastrointestinal condition of a patient;treating a patient to minimize the patient's consumption of certainsolids or liquids; reducing patient symptoms associated with tLESRwherein such reduction is measured by an improvement in a patientquality of life survey and wherein said improvement is calculated byhaving a patient provide a first set of responses to said quality oflife survey prior to treatment and having a patient provide a second setof responses to said quality of life survey after said treatment andcomparing the first set of responses to said second set of responses;treating a patient for any of the above-listed therapeutic objectiveswith the additional requirement of avoiding tissue habituation, tissuefatigue, tissue injury or damage, or certain adverse reactions,including, but not limited to, chest pain, difficulty in swallowing,pain associated with swallowing, heartburn, injury to surroundingtissue, or arrhythmias.

The disclosed treatment methods may be practiced within, and devices maybe implanted within, a plurality of anatomical regions to achieve one ormore of the therapeutic objectives described above. Treatment sites, orimplantation sites, include: the lower esophageal sphincter; within 5 cmabove and 5 cm below the LES; proximate to the LES; in the vicinity ofthe LES; the esophageal body; the upper esophageal sphincter (UES);within, proximate to, or in the vicinity of the gastro-esophagealjunction; the esophagus, including esophageal body, LES, and UES;proximate to the esophagus; in the vicinity of the esophagus; at orwithin the stomach; nerves supplying the LES or gastro-esophagealjunction; nerves supplying the esophageal body; nerves supplying theUES; or nerves supplying the esophagus, including the esophageal body,LES, and UES.

Additionally, it should be appreciated that a therapy which requires alower amount of energy increases the long-term functionality of astimulation device. Furthermore, accurate implantation of electrodes isimperative for improved efficacy and safety of these devices. Submucosaof organ systems, such as the area within the gastrointestinal tractbetween the muscularis mucosa and muscularis propria (two high impedancelayers), have a relatively lower electrode-tissue interface impedance(referred to as impedance herein) and are therefore desirable locationsfor lead implantation and improved efficacy of stimulation. In addition,the loose connective tissue of the submucosa provides an improvedenvironment for tunneling and creating pockets for lead implantation andmicrostimulator implantation.

In one embodiment, the macrostimulator, microstimulator or theirrespective electrodes are implanted in the submucosa proximate to theLES, esophagus, or UES to cause adjacent smooth muscle contraction usingelectrical field stimulation. Additional stimulator structures and/orelectrodes may be placed in the adjacent muscularis or serosa and usedin combination with the aforementioned macrostimulator ormicrostimulator. In another embodiment, the stimulator or electrodes areimplanted in the gastrointestinal submucosa to cause gastrointestinalmuscle contraction using electrical field stimulation. Additionalstimulator structures and/or electrodes may be placed or proximate to inthe adjacent gastrointestinal muscularis mucosa, gastrointestinalserosa, or gastrointestinal nerves.

Treatment Methodologies

In one embodiment, any stimulator device, including a macrostimulator ormicrostimulator, can be programmed to implement one or more treatmentprotocols disclosed herein. It should be appreciated that the treatmentmethods described below are implemented in a stimulator, such as amacrostimulator or microstimulator, having a plurality of electrodes, orat least one electrode, including, but not limited to, unipolar orbipolar electrodes, an energy source, such as a battery or capacitor,and a memory, whether local to the stimulator or remote from thestimulator and adapted to transmit data to the stimulator, which storesa plurality of programmatic instructions wherein said instructions, whenexecuted by the macro/microstimulator, execute the stimulationtherapies, as described below.

The present application is directed toward stimulation treatment methodsthat permit a patient, with one or more implanted stimulator systems asdescribed above, to engage in a swallow that causes liquid, food mass,food mass mixed with liquid, or any bolus of matter greater than 1 cc topass through the patient's esophagus (collectively referred to as a wetswallow or bolus swallow; wet swallow and bolus swallow shall be usedinterchangeably) while concurrently having one or more gastrointestinalanatomical structures, such as the upper esophagus, upper esophagealsphincter, esophagus, lower esophageal sphincter, the distal esophagus,the gastric cardia, gastric fundus, and/or the vagus nerve, or any ofthe other anatomical structures described herein, be subjected toelectrical stimulation.

The prior art has conventionally taught that stimulation ofgastrointestinal structures, particularly the esophagus and loweresophageal sphincter, must cease when a patient engages in a swallow. Ithas now been unexpectantly determined that, if stimulated appropriately,such stimulation need not cease during, concurrent with, or in responseto a patient engaging in a wet swallow. The stimulation protocols,described below, are effectuated through the stimulation devicesdescribed herein and by the patent documents incorporated herein byreference. Such devices generally include any device for electricalstimulation of one or more structures in the esophagus and for use inthe treatment of tLESR, comprising a pulse generator providingelectrical stimulation, a power source for powering the pulse generator,one or more stimulating electrodes operatively coupled or connected tothe pulse generator wherein the electrode sets are adapted to bepositioned within or adjacent to one or more anatomical structuresdescribed herein. Preferably, the stimulating electrodes are designed tobe implanted predominantly in the submucosal layer or the muscularislayer of the esophagus. In one embodiment, a plurality of electrodes inelectrical communication with a macrostimulator are implantedpredominantly in the muscularis propria. In one embodiment, a pluralityof electrodes in electrical communication with a microstimulator areimplanted predominantly in the submucosal layer, if done endoscopically,and in the muscularis layer if done laparoscopically.

In one embodiment, the stimulation parameters, which are effectuatedthrough an electrical pulse that can be of any shape, including square,rectangular, sinusoidal or saw-tooth, may comprise any of the variableranges detailed in the table below

TABLE 1 Pulse On Off Pulse Type Pulse Width Frequency Pulse AmplitudeCycle Cycle Short Pulse 1-999 μsec 1-100 Hz Low (1-999 μAmp) 0-24 hrs0-24 hrs Intermediate (1-50 mAmp) and any values therein Intermediate1-250 msec 1-100 Hz Low (1-999 μAmp) 0-24 hrs 0-24 hrs PulseIntermediate (1-50 mAmp) and any values therein Intermediate 1-250 msec1-59 cpm Low (1-999 μAmp) 0-24 hrs 0-24 hrs Pulse Intermediate (1-50mAmp) and any values therein Long Pulse 251 msec-1 sec 1-59 cpm Low(1-999 μAmp) 0-24 hrs 0-24 hrs Intermediate (1-50 mAmp) and any valuestherein

In one embodiment, the present invention is directed to a method fortreating esophageal disease by electrically stimulating a loweresophageal sphincter or nerve supplying the LES that causes improvementin the lower esophageal sphincter pressure without affecting,preventing, prohibiting, or otherwise hindering a bolus swallow inducedrelaxation of the lower esophageal sphincter or bolus swallow inducedesophageal body motility. In this embodiment, because electricalstimulation need not be inhibited, there is no need to sense for thebolus swallow in order to trigger a cessation of electrical stimulationand, therefore, a stimulator need not be programmed to sense for thebolus swallow, to modify stimulation in response to a bolus swallow(even if the stimulation device has sensing capabilities), or to beotherwise responsive to a bolus swallow.

This stimulation process normalizes lower esophageal sphincter functionbecause it improves lower esophageal sphincter pressure while notprohibiting or preventing a natural bolus swallow. This process also a)does not affect gastric distension induced relaxation of the loweresophageal relaxation, b) improves the post bolus swallow augmentationof the LES pressure, and c) improves the esophageal body function, amongother therapeutic benefits, as described above.

Having eliminated the need to dynamically control the electricalstimulation based on swallow sensing, the system can be allowed toengage in automated “on/off” duty cycles that can range from 1 second to24 hours. During the “on” period, stimulation is preferably applied fora long enough period to enable recruitment of adequate nerves and/ormuscle fibers to achieve the desired pressure, function or effect. Thedesired “on” period is patient specific and is preferably calculatedbased on the time required to change the LES pressure from baselinepressure or function to the desired therapeutic pressure or functionplus additional time to maintain the therapeutic pressure (maintenancetime) or function. In one embodiment, the maintenance time ranges from 1second to 12 hours. While sensors are not required, in one embodiment,the “on” period can be determined, or triggered by, sensors that sensechanges in the LES, such as LES pressure changes, or the esophagus.Those sensing electrodes sense one or more of change in gastrointestinalmuscle tone or impedance, peristaltic activity, esophageal peristalsis,esophageal pH, esophageal pressure, esophageal impedance, esophagealelectrical activity, gastric peristalsis, gastric electrical activity,gastric chemical activity, gastric hormonal activity, gastrictemperature, gastric impedance, electrical activity, gastric pH, bloodchemical and hormonal activity, vagal or other gastrointestinal neuralactivity and salivary chemical activity and can be preferably positionedin or adjacent one or more of the esophagus, the stomach, the smallintestine, the colon, the vagus or other gastrointestinal nerves and thevascular system.

The “off” period is preferably set in order to prevent development oftolerance or muscle fatigue, to improve device functionality, and tooptimize energy consumption from the battery. The desired “off” periodranges from 1 second to 24 hours. The desired “off” period is patientspecific and calculated based on the time required to change the LESpressure or function from the desired therapeutic pressure or functionto the baseline pressure or function plus optional additional time tomaintain the baseline pressure (relaxation time) or function. In oneembodiment, the relaxation time ranges from 1 second to 12 hours. Whilesensors are not required, in one embodiment, the “off” period can bedetermined, or triggered by, sensors that sense changes in the LES, suchas pressure, or the esophagus. Those sensing electrodes sense one ormore of change in gastrointestinal muscle tone or impedance, peristalticactivity, esophageal peristalsis, esophageal pH, esophageal pressure,esophageal impedance, esophageal electrical activity, gastricperistalsis, gastric electrical activity, gastric chemical activity,gastric hormonal activity, gastric temperature, gastric impedance,gastric pH, blood chemical and hormonal activity, vagal or othergastrointestinal neural activity and salivary chemical activity and canbe preferably positioned in or adjacent one or more of the esophagus,the stomach, the small intestine, the colon, the vagus or othergastrointestinal nerves and the vascular system.

Accordingly, in one embodiment, stimulation can be provided for a firstperiod to generate a LES pressure, function or esophageal function of afirst threshold level, then the stimulation can be lowered or removedwhile still maintaining LES pressure, function or esophageal function ator above the first threshold level of LES pressure, function oresophageal function, thereby treating tLESR and other gastrointestinalindications. Stimulation of greater than a first threshold level of LESpressure can be delivered within a time period of less than a first timeperiod, thereby treating certain gastrointestinal indications. In oneembodiment, the present specification discloses a treatment method inwhich stimulation, such as at or under 30 mAmp, 15 mAmp, 10 mAmp, 8mAmp, or any increment therein, is applied to achieve a LES pressure ofless than a first threshold level and, concurrently, wet swallows arestill enabled without terminating or decreasing the stimulation. In oneembodiment, the present specification discloses a treatment method inwhich stimulation, such as at or under 30 mAmp, 15 mAmp, 10 mAmp, 8mAmp, or any increment therein, is applied and then terminated, afterwhich LES pressure function or esophageal function increases beyond afirst threshold level and, concurrently, wet swallows are still enabled.It should be appreciated that the stimulation parameters can bepresented in terms of total energy applied. For example, the currentstimulation parameters can be replaced, throughout this specification,with preferred energy levels, such as at or under 6 mC, 3 mC, 1 mC, 0.08mC, or any increment therein.

It should further be appreciated that the treatment methodologiesdisclosed herein adjust for, take advantage of, account for, orotherwise optimally use a delayed, or latent, pressure response from theLES in response to electrical stimulation. Conventionally, the prior arthas taught that the LES instantaneously responds, either by contractingor relaxing, to the application of, or removal of, electricalstimulation. In the present treatment methodologies, the LES has adelayed or latent response to electrical stimulation, thereby resultingin a gradual increase in LES pressure after the application ofelectrical stimulation and a sustained heightened level of LES pressureafter electrical stimulation is terminated, at least for certainstimulation parameters. Accordingly, a desired normalization of LESpressure or tone can be achieved well in advance of an expected tLESRtriggering event, such as eating, sleeping, napping, laying down, beingin a supine position, bolus swallowing, or engaging in physicalactivity, by applying electrical stimulation before the tLESR triggeringevent and then terminating the stimulation prior to, during, or afterthe tLESR triggering event. Multiple embodiments of the presentinvention take advantage of this delayed response by stimulating the LESin a manner that does not cause immediate contraction of the musculatureor an immediate increase in LES pressure. For example, in oneembodiment, stimulation is directed to the LES at a level of no morethan 6 mC repeated on a regular basis, for example 20 times a second,for a specific period of time, for example 30 minutes. This results incontraction of the LES and a rise in LES pressure that does not occuruntil after the initial 5 minutes of stimulation and that continues oncestimulation has been terminated. In one embodiment, stimulation isdirected to the LES at a level of no more than 6 mC repeated on aregular basis, for example 20 times a second, for a specific period oftime, for example 30 minutes. This results in contraction of the LES anda rise in LES pressure that does not occur until after the initialstimulation initiated and that continues or persists once stimulationhas been terminated.

In these stimulation methodologies, a sub-threshold stimulation thatdoes not generate an instantaneous LES or esophageal function responseis applied for a predefined duration of time to achieve a therapeuticresponse. In one embodiment, a sub-threshold stimulation means that anapplied stimulation does not substantially instantaneously achieve acontraction. A sub-threshold stimulation may have stimulation parametersof less than 20 mAmp, less than 10 mAmp, or less than 8 mAmp. In oneembodiment, a threshold or above threshold stimulation means that anapplied stimulation substantially instantaneously achieves a contractionand may have stimulation parameters of greater than 20 mAmp, greaterthan 10 mAmp, or greater than 8 mAmp. Sub-threshold stimulation hasmultiple advantages, including improved device functionality, improvedenergy transfer in a wireless microstimulator, improved patient safety,decreased patient adverse symptoms or side effects and decreasedtolerance and/or fatigue.

Referring to FIG. 1, a normal esophageal pressure profile 100 is shown.With deglutition, the peristaltic wave follows immediately after the UESrelaxation, producing a lumen-occluding contraction of the esophagealcircular muscle. The contraction wave migrates aborally at a speed thatvaries along the esophagus. The peristaltic velocity averages about 3cm/sec in the upper esophagus, then accelerates to about 5 cm/sec in themid-esophagus, and slows again to approximately 2.5 cm/sec distally. Theduration and amplitude of individual pressure waves also varies alongthe esophagus. The duration of the wave is shortest in the proximalesophagus (approximately 2 seconds) and longest distally (approximately5 to 7 seconds). Peak pressures average 53±9 mmHg in the upperesophagus, 35±6 mmHg in the mid-portion, and 70±12 mmHg in the loweresophagus. These parameters can be influenced by a number of variablesincluding bolus size, viscosity, patient position (e.g., upright vs.supine), and bolus temperature. For instance, a large bolus elicitsstronger peristaltic contractions that migrate distally at a slower ratethan a small bolus. The peristaltic velocity is also slowed by outflowobstruction or increases in intra-abdominal pressure. Warm boluses tendto enhance, whereas cold boluses inhibit the amplitude of peristalticcontractions.

Accordingly, bolus 102 propagates through the UES 112, esophageal body115, and LES 117 over a period of approximately, and typically, tenseconds. As the bolus 102 moves through, portions of the UES 112,esophageal body 115, and LES 117 experience an increase in pressure. Ina normal person, the baseline pressure range for the UES 112 is between34 and 104 mmHg, for the esophagus 115 is between 30 and 180 mmHg, andfor the LES 117 is between 10 and 45 mmHg. At the point of LESrelaxation 110, which occurs to permit the bolus to pass through intothe stomach, the LES pressure decreases to below approximately 8.4 mmHg.Notably, in a normal patient, post-swallow, the LES pressure increases,after having decreased for the swallow, and then remains at a higherbaseline pressure level than just immediately prior to the swallow.

In one embodiment, the presently disclosed methods and systems return anabnormally functioning LES to a state of normalcy, post-stimulation orpost initiation of stimulation. The treatment methodology comprisesimplanting a stimulation device, as described herein, and electricallystimulating the device to cause an increased LES pressure, in accordancewith any of the stimulation methodologies described herein. Afterstimulation is terminated, one or more of the following functionalparameters, characteristic of an abnormally functioning LES, achievesnormal physiological range: a) LES basal pressure (respiratory minima)returns to a range of 15-32 mmHg, b) LES basal pressure (respiratorymean) returns to a range of 10-43 mmHg, c) LES residual pressure returnsto a range of less than 15 mmHg, d) LES percent relaxation returns to arange of greater than 40%, e) LES duration of contraction returns to arange of 2.9 seconds to 5.1 seconds (3 cm above the LES), 3 seconds to 5seconds (8 cm above the LES), or 2.8 seconds to 4.2 seconds (13 cm abovethe LES), f) lower esophageal acid exposure during 24-hour pH-metryreturns to a range of pH<4 for less than 10%, and preferably less than5%, of total or less than 8% or preferably less than 3% of supine time,and/or g) esophageal reflux events return to less than 100 per 24 hourperiod or reduce by 50% as documented by impedance pH monitoring, i)normal bolus swallows return with complete bolus transit, defined asdetection of bolus exit in all 3 of the distal impedance channels and/orj) esophageal pH returns to a range equal to twice the normal, asdefined in the table below or any normative standards for the measuringdevice.

TABLE 2 Catheter-based dual-probe (distal and proximal) esophageal pHmonitoring Variable Normal Time pH <4.0 (%) Proximal (%) Distal (%)Total period <0.9 <4.2 Upright period <1.2 <6.3 Recumbent period <0.0<1.2 Distal = 5 cm above manometric defined proximal border of the LES.Proximal = 20 cm above manometric defined proximal border of the LES.Catheter free distal esophageal pH monitoring Variable Normal Time pH<4.0 (%) Distal (%) Total period <5.3 Upright period <6.9 Recumbentperiod <6.7 Distal = 6 cm above endoscopic defined gastroesophagealjunction

Accordingly, the presently disclosed methods and systems modify one ormore of the aforementioned functional parameters characteristic of anabnormally functioning LES or the esophagus to that of a normally orimproved functioning LES or the esophagus, even after stimulation isterminated. By transforming an abnormally functioning LES or theesophagus to a normally or improved functioning LES or the esophagus,esophageal reflux, tLESR, esophageal motility disorders or esophagealneural, muscular or neuromuscular disorders, can be effectively treated.

In another embodiment, the presently disclosed methods and systemsmodify an abnormally functioning LES or the esophagus to provide for anadequately functioning LES or the esophagus post-stimulation. Thetreatment methodology comprises implanting a stimulation device, asdescribed herein, and electrically stimulating the tissue to cause anincrease in LES pressure, in accordance with any of the stimulationmethodologies described herein. After stimulation is terminated, one ormore of the following functional parameters, characteristic of anabnormally functioning LES, returns to a physiological range sufficientto prevent esophageal reflux, tLESR, esophageal motility disorders oresophageal neural, muscular or neuromuscular disorders: a) LES basalpressure, b) LES residual pressure, c) LES percent relaxation, d) LESduration of contraction, e) distal esophageal pH, f) esophageal refluxevents, and g) esophageal body function. Accordingly, the presentinvention modifies physiological parameters characteristic of anabnormally functioning LES, relative to the patient's pre-treatmentstate, to that of an adequately functioning LES, even after stimulationis terminated. By transforming an abnormally functioning LES to anadequately functioning LES, esophageal reflux, tLESR, esophagealmotility disorders or esophageal neural, muscular or neuromusculardisorders can be effectively mitigated.

In another embodiment, the present invention improves the LES pressureprofile of an abnormally functioning LES post-stimulation. The treatmentmethodology comprises implanting a stimulation device, as describedherein, and electrically stimulating the tissue to cause an increase inLES pressure, in accordance with any of the stimulation methodologiesdescribed herein. After stimulation is terminated, LES basal pressure isimproved, relative to the patient's pre-treatment state, by at least 5%,preferably 10%. Accordingly, the presently disclosed methods and systemsmodify the pressure profile of an abnormal functioning LES, even afterstimulation is terminated. By doing so, esophageal reflux, tLESR,esophageal motility disorders or esophageal neural, muscular orneuromuscular disorders can be effectively mitigated.

In another embodiment, the presently disclosed methods and systemsimprove, post-stimulation, at least one of a) esophageal body pressure,b) esophageal body contractility, c) esophageal body motility, d)esophageal body bolus transit, or e) esophageal body peristalsis,resulting in improved esophageal acid clearance after a reflux event,decreasing esophageal acid exposure time, and minimizing damage fromexposure of esophageal mucosa to gastro-duodenal refluxate. Thetreatment methodology comprises implanting a stimulation device, asdescribed herein, and electrically stimulating the tissue to cause anincrease in LES pressure, in accordance with any of the stimulationmethodologies described herein. After stimulation is terminated, atleast one of a) esophageal body pressure, b) esophageal bodycontractility, c) esophageal body motility, e) esophageal body bolustransit, or f) esophageal body peristalsis improves and remains in animproved state while the stimulator is off.

In another embodiment, the presently disclosed methods and devicesachieve any of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the patient's esophagushas a function, and treating the patient by applying electricalstimulation, wherein the stimulation causes an improvement in esophagealfunction. Esophageal function may include any one of esophagealpressure, bolus transit, esophageal perception, esophageal accommodationor esophageal clearance of the refluxate.

In another embodiment, the presently disclosed methods and devicesachieve any of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the patient's esophagushas a function, and treating the patient by applying electricalstimulation, wherein the stimulation causes a non-instantaneous ordelayed improvement in esophageal function. Esophageal function mayinclude any one of esophageal pressure, bolus transit, esophagealperception, esophageal accommodation or esophageal clearance of therefluxate.

Referring to FIG. 2, in a typical tLESR patient, the LES relaxes priorto swallow 205. Post-swallow, the LES increases pressure 210, which canbe observed for a short duration following the swallow, and then revertsto a resting tone 215. It should be appreciated, however, that theresting tone 215 is too low to prevent reflux. Referring to FIG. 3, theresting tone 315, both before and after the relaxation 310 associatedwith a bolus swallow, is significantly increased using the devices andmethodologies of the present invention, while still keeping intact therelaxation function 310. This represents a significant improvement overtreatments that closed the LES and did not allow the muscle to properlyrelax during swallows, absent termination of stimulation.

Referring to FIGS. 4-7, the presently disclosed methods and systemsenable different post-stimulation residual effects, including anincrease in LES pressure post-stimulation 410 followed by a decrease inLES pressure down to a stimulation state 405 over a period of 2 to 3hours (FIG. 4), a slow decrease in LES pressure post-stimulation 510back to a pre-stimulation LES pressure level 505 over a period of 1 to 2hours (FIG. 5), a continued increase in LES pressure post-stimulation610 followed by a decrease in LES pressure which still remains above apre-stimulation state 605 after a period of 2 to 3 hours (FIG. 6), andminimal to no increase in LES pressure during stimulation 705 and acontinued increase in LES pressure post-stimulation 710 followed by adecrease in LES pressure which still remains above a pre-stimulationstate after a period of 2 to 3 hours (FIG. 7).

Accordingly, in one embodiment, the present invention encompasses amethod for controlling muscle action using electrical stimulation by amodulated electrical signal having carrier frequency in the range of 2KHz-100 KHz and an on-off modulating signal having an “on” duration inthe range of 5 μs to 500 msec and, in particular, 200 μs.

In one embodiment, a pacemaker lead, such as a modified Medtronic 6416200 cm, is secured to the LES in a submucosal tunnel using endoclipsalong the body of the lead and exteriorized nasally. Stimulation isapplied using a 200 μsec to 3 msec pulse with a pulse amplitude of 1mAmp to 15 mAmp, more preferably 5 mAmp to 10 mAmp, pulse frequency ofpreferably less than 1 msec, more preferably 200 μs, and a pulse widthof 200 μsec. The patient's resting LES pressure, which is greater thanor equal to 5 mmHg, is thereafter increased by at least 5%, morepreferably 25-50%. Additionally, transient LES relaxation is improved byat least 5%, LES function is improved by at least 5%, esophageal bodypressure is improved by at least 5%, esophageal body function isimproved by at least 5%, symptoms of tLESR are improved by at least 5%,esophageal acid exposure is improved by at least 5%, quality of life isimproved by at least 5%, caloric intake is improved by at least 5%,and/or weight is improved by at least 5%.

These improvements are achieved without any affect on patient's swallowfunction, adverse symptoms, or cardiac rhythm disturbances. Theseimprovements are also achieved by avoiding continuous electricalstimulation, which yields problems of muscle fatigue, build up oftolerance, tissue damage, and excessively high requirements for localenergy storage, such as capacitor size or battery life.

In another embodiment, the stimulator may be operated using a pulsehaving a frequency of 20 Hz (1-100 Hz), a pulse amplitude of 1 μAmp-1Amp, more preferably 1-20 mAmp, and a pulse width of 1 μsec-1 msec, andmore preferably 100-500 μsec. The stimulator may also be stimulatedusing a pulse having a frequency of 20 Hz (1-100 Hz), a pulse amplitudeof 1-20 mA (1 μAmp-1 Amp), and a pulse width of 1-50 msec (500 μsec-100msec). The stimulator may also be stimulated using a pulse having afrequency of 5 cpm (1-100 cpm), a pulse amplitude of 1-20 mAmp (1 μAmp-1Amp), and a pulse width of 100-500 msec (1 msec-1 sec).

In certain applications, there is an advantage to combining neuralstimulation with direct muscle stimulation. Such applications include,for example, gastric stimulation for gastroparesis where a combinedeffect on gastric muscle and neural modulation can be synergistic inimproving both gastric emptying rates and symptoms associated withgastroparesis. Another example can be the treatment of chronic refluxdisease where both high frequency and low frequency pulses can havedesirable effects on maintaining adequate lower esophageal sphinctertone or function while modulating the perception of symptoms associatedwith tLESR.

In certain applications where an implantable electrode or a leadlessdevice is used for delivering electrical stimulation, it is technicallymore feasible to apply lower pulse width (having higher frequencycomponents) than signals having wider pulse duration. The reason is thatirreversible electrochemical effects occur when the total chargetransfer through the electrode-tissue interface at any given timeincreases above a certain threshold. In these cases electrolysis occurswhich releases metal ions into the tissue, damages the electrode, andcauses dangerous pH changes in the local tissue. This has negativeeffects on the electrode longevity and on the tissue and should beavoided especially in chronic applications where stimulation of the samesite using the same electrode or device is planned for an extendedperiod of time.

Some methods for overcoming the problems of using long pulse durationswere developed that attempt to enhance the capacitance of theelectrode-tissue interface so as to increase the threshold forirreversible effects thereby increasing the maximal pulse width that canbe used chronically. Electrode capacitance can be increased in variousways, such as by enhancing effective electrode surface area by coating(e.g. coating with iridium-oxide or titanium nitride), by changing theelectrode material, and/or by geometrical changes in the electrodeshape. These methods, however, have some undesirable consequences, suchas a significant increase in the manufacturing cost of the electrodeand/or making the electrode unsuitable for specific implantationprocedures. It is therefore useful to minimize the use of long pulsedurations.

Furthermore, it should be noted that the use of square wave pulses,which is very common in conventional electrical stimulation systems,contains energy in frequency bands that are higher than the base rate ofthe pulse width. In general, when a square wave is used then most of theenergy is delivered in the base rate and a portion of the energy isdelivered in frequencies that are multiples (harmonics) of such baserate. Consequently, when a wide pulse width is delivered at a lowfrequency rate, some energy is also delivered in higher bands (multiplesof the base rate) and also multiples of the reciprocal value of thepulse width. The practical effect, however, of these higher frequencycomponents (or harmonics) is relatively small since only a small portionof the energy is delivered in these bands. It should further beappreciated that some frequencies, especially very high ones, are notabsorbed in most tissues and can therefore be used as carriers to lowerfrequency signals that modulate them. Accordingly, high frequencies canbe used to transfer or carry energy to the tissue without anyphysiological effect. Recovery of the low frequency signal is performedusing a demodulator.

In light of the above, in one embodiment, a combination of low and highfrequency signals (e.g. a waveform including both a high frequencycomponent and a low frequency component) are delivered through anelectrode or a leadless stimulating device with the purpose of applyingtwo separate effects to the stimulated tissue and positively impactinglower esophageal sphincter tone. The low frequency signal will bemodulated on a high frequency carrier known to be neutral to muscle tonewhereas the low frequency signal will be demodulated by the tissueitself and deliver a separate impact on the tissue, which is known tooccur with a direct muscle stimulation using low frequency signals. Thesignal is designed to have a zero net charge delivered to the tissueover durations shorter than lms thereby allowing flexibility inelectrode design far more than what would be required if using a longpulse duration directly.

In one embodiment, referring to FIG. 8, the modulation is achieved bypulse trains having a base high frequency and duration equal to thedesired long pulse width. Here, the stimulation train does not have anet zero charge; therefore, in order to discharge the electrode-tissuecapacitance, a 350 msec time period can be deployed, using a lowimpedance pathway switched by the stimulation device. Alternatively, asingle negative discharging pulse can be applied once every 700 mseccycle. The low impedance connection can also preferably be appliedfollowing each of the 100 μsec pulses thereby minimizing the maximal netcharge accumulated on the electrode-tissue capacitance. There areseveral advantages of this waveform configuration: 1) the longest pulseduration applied is 100 μsec thereby relaxing the demands on achronically implantable electrode capacitance that would have beenrequired for a 350 msec pulse duration; 2) a train duration of 350 msecadds a low frequency component which is known to have a direct positiveeffect on muscle tone; 3) there is a reduced energy requirement from thedevice, resulting from the lower total pulse durations; and 4) the totalstimulation result is optimized by a combination of two differentfrequency bands, each controlling the muscle through an independentphysiological mechanism.

In another embodiment, the present invention encompasses an apparatuscomprising a housing, pulse generator capable of generating square wavesin the frequency range of 2 KHz-100 KHz, conductive tissue interface,means for fixation of conductive tissue interface to muscle tissue,programmable control unit capable of delivering said pulse generatoroutput to the tissue intermittently whereas each “on” duration can beprogrammable in the range of 5 μsec to 500 msec and an “off” durationprogrammable in the same or different range. Optionally, the muscletissue is the LES, esophagus, or UES. Optionally, the carrier frequencyis in the range of 40 KHz-60 KHz and “on” duration is 300-400 msec.Optionally, the signal structure may be triggered by other timingmechanisms, including various patient-specific attributes, activities,and states. Optionally, a control unit, which is separate from amicrostimulation device, includes a demodulator and a pulse generatorfor the high frequency carrier, transmits energy to the microstimulatorto power the pulse generator, and includes modulation information usinga different carrier frequency. Optionally, the stimulation devicecomprises multiple leads output and alternates a modulation signalbetween two or more stimulation locations where, while one location hasan “on” state, the other location has an “off” state, and vice-versa.

In another embodiment, the stimulator may be stimulated using an “on”phase and an “off” phase, wherein the on phase is between 1 minute and 1hour and the off phase is between 1 minute and 1 hour. Preferably, boththe on and off phases are between 5 and 30 minutes. In anotherembodiment, the stimulator or microstimulator may be stimulated using acombination of a low frequency pulse and an intermediate or highfrequency pulse. In one embodiment, the low frequency pulses aredelivered for a duration that is 1% to 1000% of the intermediate or highpulse duration.

In another embodiment, the stimulator may be stimulated using an “on”phase and an “off” phase, wherein the on phase is between 1 second and24 hours and the off phase is between 1 second and 24 hours. Preferably,the off phase is longer than the on phase. In this embodiment, thestimulator or microstimulator may be stimulated using a combination of alow frequency pulse and an intermediate or high frequency pulse. In oneembodiment, the low frequency pulses are delivered for a duration thatis 1% to 1000% of the intermediate or high pulse duration. In anotherembodiment a combination of same frequency pulse with varying amplitudecan be used. For example a patient can receive intermittent orcontinuous stimulation at a lower amplitude with one or more session ofstimulation at a higher amplitude where the high amplitude is at leasttwice the low amplitude.

It should be appreciated that, wherever stimulation parameters aredescribed, the stimulation may be initiated by “ramping up” to thestated stimulation levels or may be terminated by “ramping down” to anoff state. The ramp up and ramp down can be as slow or as fast asrequired to effectuate the required therapy.

In one embodiment, the programmed duty cycle, pulse frequency, pulsewidth, pulse amplitude of the stimulator and corresponding electrodeconfiguration are configured to trigger secretion of neurokinin A (NKA)or a similar peptide. The configuration of the frequency and amplitudeis set to efficiently achieve a clinically significant secretion withminimal energy. The session duration can make use of the longdegradation time of NKA and be configured to turn off stimulationfollowing the expected accumulation of sufficient NKA secretion.Electrode configuration, as further described below, can be adapted sothat the desired optimal session duration will alternate in differentregions using implantation of electrodes in different regions of theLES. The configuration of the stimulation to impact local NKA level canbe designed to achieve the required pressure curve as described in FIGS.4-7.

It should further be noted that because the stimulation device enablesthe therapeutically effective treatment of a plurality of ailments, asdescribed above, at currents below 15 mAmp, one can avoid subjecting thepatient to physical pain, sensation, or discomfort. The present systemcan achieve the therapeutic goals and effectively operate by deliveringlower stimulation levels for longer periods of time, such as bydelivering 3 mAmp for 10 minutes rather than 15 mAmp for 5 minutes. Thepulse frequency can be 20 Hz and the stimulation can be delivered lessthan five times per day, such as three times per day.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device, such as a macrostimulator ormicrostimulator, adapted to be implanted within the patient's loweresophageal sphincter and adapted to apply electrical stimulation to thepatient's lower esophageal sphincter; and programming, using, oroperating said stimulation device, wherein said programming, use, oroperation defines, uses, or is dependent upon a plurality of stimulationparameters that determine the application of electrical stimulation tothe patient's lower esophageal sphincter and wherein said stimulationparameters are selected, derived, obtained, calculated, or determined,at least in part, to account for a latent, delayed, time-delayed, orfuture response of the patient's lower esophageal sphincter.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter and to apply electrical stimulationto the patient's lower esophageal sphincter, wherein said loweresophageal sphincter exhibits a latent, delayed, time-delayed, or futureresponse to applied electrical stimulation; and treating said patient byapplying electrical stimulation based upon derived from, or dependentupon said latent, delayed, time-delayed or future response.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter and to apply electrical stimulationto the patient's lower esophageal sphincter; and initiating, activating,beginning, or starting said electrical stimulation prior to apre-defined or fixed time wherein said pre-defined or fixed time isassociated with a GERD triggering event and wherein said initiationoccurs prior to said pre-defined or fixed time by a minimum period, suchas at least 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2hours, 3 hours, 12 hours, 24 hours, or any time increment therein.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter and adapted to apply electricalstimulation to the patient's lower esophageal sphincter; and initiating,activating, beginning, or starting said electrical stimulation prior toa pre-defined or fixed time wherein said pre-defined or fixed time isassociated with a GERD triggering event and wherein said initiationoccurs prior to said pre-defined or fixed time by a minimum period, suchas at least 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2hours, 3 hours, 12 hours, 24 hours, or any time increment therein; andterminating said electrical stimulation after said pre-defined or fixedtime has passed.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter and adapted to apply electricalstimulation to the patient's lower esophageal sphincter; andprogramming, using, or operating said stimulation device, wherein saidprogramming, use, or operation defines, uses, or is dependent upon aplurality of stimulation parameters that determine the application ofelectrical stimulation to the patient's lower esophageal sphincter andwherein said stimulation parameters are selected, derived, obtained,calculated, or determined, at least in part, to treat GERD withoutinhibiting, hindering, stopping, or preventing the patient fromswallowing.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation while the patient swallows, duringperiods of esophageal motility, or during esophageal peristalsis.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation in accordance with a preset period andwherein said preset period is not dependent upon, influenced by,modified by, lengthened by, or shortened by a physiological state of apatient.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation in accordance with a preset period andwherein said preset period is not dependent upon, influenced by,modified by, lengthened by, or shortened by the patient swallowing,esophageal motility, esophageal peristalsis, or being in a feedingstate.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation that is not dependent upon, influencedby, modified by, lengthened by, or shortened by a physiological state,biological parameter, sensed physiological or biological parameters of apatient.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation that is not dependent upon, influencedby, modified by, lengthened by, or shortened by the patient swallowing,esophageal motility, esophageal peristalsis, or being in a feedingstate.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingsufficient electrical stimulation to increase said pressure but not toinhibit, hinder, stop, or prevent swallowing, esophageal motility,esophageal peristalsis, or being in a feeding state.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the lower esophagealsphincter has a function, and treating the patient by applyingsufficient electrical stimulation to improve the function but not toinhibit, hinder, stop, or prevent swallowing, esophageal motility, oresophageal peristalsis or dissuade a patient from being in a feedingstate.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes an increase insaid pressure of at least 5% only after an elapsed period of time of atleast one minute.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation improves or normalizeslower esophageal function, improves or normalizes LES pressure, orincreases LES pressure to a normal physiological range only after anelapsed period of time or only after a delay of at least one minute.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes anon-instantaneous or delayed increase in said pressure.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the lower esophagealsphincter has a function, and treating the patient by applyingelectrical stimulation, wherein the stimulation causes anon-instantaneous or delayed improvement in the function.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes anon-instantaneous or delayed increase in said pressure and wherein saidnon-instantaneous or delayed increase in the pressure normalizes LESfunction, normalizes LES pressure, increases LES pressure to a normalphysiological range, or increases LES pressure by at least 3%.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes a gradualincrease in said pressure.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes an increase insaid pressure after said electrical stimulation is terminated.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation having a first level, wherein said stimulationcauses an increase in said pressure after said electrical stimulation isdecreased from said first level.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by improving thepressure or function of the patient's lower esophageal sphincter.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives, wherein said patienthas a lower esophageal sphincter and wherein said lower esophagealsphincter has a pressure, by increasing the pressure of the patient'slower esophageal sphincter through the application of electricalstimulation to the lower esophageal sphincter or areas proximatethereto.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives, wherein said patienthas a lower esophageal sphincter and wherein said lower esophagealsphincter has a pressure, by increasing the pressure of the patient'slower esophageal sphincter through the application of electricalstimulation to the lower esophageal sphincter or areas proximatethereto, and wherein said pressure does not inhibit or otherwise hinderthe patient's ability to swallow.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by modifying thepressure or function of the patient's lower esophageal sphincter.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by modifying thepressure or function of the patient's lower esophageal sphincter throughthe application of electrical stimulation to the lower esophagealsphincter or areas proximate thereto.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by modifying thepressure or function of the patient's lower esophageal sphincter throughthe application of electrical stimulation to the lower esophagealsphincter or areas proximate thereto and wherein said pressure does notinhibit or otherwise hinder the patient's ability to swallow.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation in accordance with at least one onperiod, wherein said on period is between 1 second and 24 hours and isnot triggered by, substantially concurrent to, or substantiallysimultaneous with an incidence of acid reflux, and at least one offperiod, wherein said off period is greater than 1 second.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation, wherein a pulse amplitude from a singleelectrode pair ranges from greater than or equal to 1 mAmp to less thanor equal to 8 mAmp.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation having a pulse duration of approximately200 μsec.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation having a pulse duration of approximately1 msec.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation having a pulse energy level of <10 mAmp,pulse duration of <1 second, and/or pulse frequency of <50 Hz.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation having a pulse energy level of 1 mAmp to10 mAmp (preferably 1 mAmp), pulse duration in a range of 50 μsec to1msec (preferably 215 μsec), a pulse frequency of 5 Hz to 50 Hz(preferably 20 Hz), pulse on time in a range of 10 minutes to 120minutes (preferably 30 minutes), and/or pulse off time in a range of 10minutes to 24 hours.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation to increase LES pressure above abaseline or threshold LES pressure, wherein said LES pressure remainsabove said baseline or threshold LES pressure after termination ofelectrical stimulation.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation to increase LES tone above a thresholdLES tone, wherein said LES tone remains above said threshold LES toneafter termination of electrical stimulation.

In one embodiment, the presently disclosed methods and devices provide amacrostimulator programmed, adapted to, or configured to perform any ofthe aforementioned methods or treatment protocols.

In one embodiment, the presently disclosed methods and devices provide amacrostimulator comprising at least one electrode, an energy source, anda pulse generator in electrical communication with the at least oneelectrode and energy source, wherein said pulse generator is programmed,adapted to, or configured to perform any of the aforementioned methodsor treatment protocols.

In one embodiment, the presently disclosed methods and devices provide amicrostimulator programmed, adapted to, or configured to perform any ofthe aforementioned methods or treatment protocols.

In one embodiment, the presently disclosed methods and devices provide amicrostimulator comprising at least one electrode, an energy source, anda pulse generator in electrical communication with the at least oneelectrode and energy source, wherein said pulse generator is programmed,adapted to, or configured to perform any of the aforementioned methodsor treatment protocols.

Such treatment methods may be combined, directed toward any of theaforementioned therapeutic objectives, and/or implemented throughstimulating any of the aforementioned anatomical areas. The treatmentmethods may be further modified by using specific stimulationparameters, open loop data processes, closed loop data processes, thepatient's physical position and degree of activity, the patient's eatingstate, timing, quantity or content thereof, certain physiologicalparameters sensed by the device, including LES pressure, oranti-habituation methods to prevent anatomical habituation to a specificset of stimulation parameters. Additionally, because the device canoperate on a time-based schedule, not necessarily physiological triggers(although a physiological trigger can be an optional embodiment),stimulation schedules can be tailored to user behavior and/or routine.For example, stimulation therapy can be delivered or stimulation energycan be transmitted at times that are most convenient, least disruptiveto the patient's activities of daily living, such as only schedulingstimulation while the patient is sleeping, relaxing, or watching TV andscheduling stimulation only after mealtimes. Such additional embodimentsare described below.

Open Loop Programming

In one optional embodiment, the stimulation parameters, including pulsewidth, pulse frequency, pulse amplitude, ramp rates, and/or duty cycle,can be modified by a physician using data sensed by, stored within, ortransmitted from the stimulation device, data sensed by, stored within,or transmitted from a sensor implanted in the patient, and/or datacaptured by an external computing device used by a patient. A stimulatordevice having a local memory, or a transmitter capable of communicatingsensed information to a remotely located memory or memory external tothe patient, captures a plurality of sensed data, as discussed ingreater detail below. Concurrently, a patient controlled computingdevice, such as a laptop, personal computer, mobile device, or tabletcomputer, which is external to the patient is used by the patient tostore data input by the patient relevant to evaluating, monitoring, andadjusting the operation of the stimulator. Both the stimulator captureddata and patient inputted data is then transmitted to a physiciancontrolled device, as described below, to enable the physician toproperly evaluate, monitor, and modify the stimulation parameters.

In one embodiment, the patient-controlled computing device comprises aplurality of programmatic instructions that, when executed, generate adisplay which prompts a user for, and is capable of receiving input fromthe user, information regarding the user's food intake, the timing ofsuch food intake, exercise regimen, degree and extent of physicalsymptoms, incidents of acid reflux, when the user sleeps, when the userlays down, type of food being consumed, quantity of food, among othervariables. This data can be captured and stored locally and/ortransmitted to a remote server for access by a physician. If accessedremotely by a physician, the physician can transmit alerts back to thepatient, via a network in communication with the computing device orconventional communication systems, such as email, text messaging orphone, to confirm dose amounts, patient state information, or providefor therapy adjustment.

In one embodiment, the stimulator captured data includes whatstimulation parameters were used and when, the sensed LES pressureprofile, including the percentage or amount of time the LES pressure wasbelow a certain threshold level, such as 10 mmHg, or above a 2^(nd)threshold level, such as 20 mm Hg, the occurrence of t-LESRs, esophagealpH, supine events, degree of physical movement, among other variables.

The patient-inputted data, when combined with the stimulator captureddata, can provide a holistic view of the patient's condition and theefficacy of a stimulation regimen. In particular, as patient symptomsare mapped to stimulation parameters and analyzed in relation to food ordrink intake, sleep, and exercise regimens, a physician will be able todetermine how best to modify the stimulation parameters, including dutycycle, stimulation initiation times or triggers, stimulation terminationtimes or triggers, pulse width, pulse amplitude, duty cycle, ramp rates,or pulse frequency, to improve patient treatment. As further discussedbelow, the physician will receive both the patient-captured andstimulation device captured data into a diagnostic terminal that can beused to process the information and transmit new stimulation parameters,if necessary, to the stimulation device. For example, the physician canmodify the stimulation parameters in a manner that would lower theincidents of reported acid reflux, generalized pain, pain whileswallowing, generalized discomfort, discomfort while swallowing, or lackof comfort during sleeping or physical exercise. The physician can alsomodify the stimulation parameters, including the initiation andtermination of stimulation, to better match one or more tLESR triggeringevents, such as eating, sleeping, lying down, or engaging in physicalactivity. The physician can also modify the stimulation parameters,including the initiation and termination of stimulation, to better matchthe patient's personal work or vacation schedule.

Additionally, alerts can be created that can be either programmed intothe patient-controlled device or stimulation device which serve tonotify the patient of a device malfunction, a recommendation to take adrug, a recommendation to come back for a checkup, among othervariables. Those alerts can also be transmitted, via a computingnetwork, to the physician. Furthermore, external data sources, such asdemographic data or expert protocols, can be integrated into thephysician system to help the physician improve the diagnostic andevaluation process and optimize the programmed set of stimulationparameters.

It should further be appreciated that, as the patient controlled deviceand stimulator device accumulate data that maps the therapeutic regimenagainst the patient's activities and symptoms, the patient controlleddevice will be able to determine, and therefore inform the patient of,patterns which tend to increase or decrease the incidents of tLESR,including types of food, quantity of food, timing of eating, among othervariables.

Closed Loop Programming

In one optional embodiment, the stimulation parameters, including pulsewidth, pulse frequency, pulse amplitude, initiation of stimulation,triggers for stimulation, termination of stimulation, triggers toterminate stimulation, ramp rates, and/or duty cycle, can be dynamicallyand intelligently modified by the stimulation device using data sensedby, stored within, or transmitted from the stimulation device, datasensed by, stored within, or transmitted from a sensor implanted in thepatient, and/or data captured by, stored within, and/or transmitted froman external computing device used by a patient.

As discussed above, data maybe captured by a patient-controlled deviceand/or the stimulator device. In this embodiment, a stimulator isfurther programmed to intelligently modify stimulation parameters,without physician input, based upon sensed data and/or patient inputs.In one embodiment, a stimulator determines that LES pressure or functionfails to improve above a predefined threshold, even after a predefinedamount of stimulation, and, accordingly, automatically modifies thestimulation parameters, within a preset range of operation, to yield animprovement in LES pressure increase. In one embodiment, a stimulatordetermines that LES pressure or function improves significantly above apredefined threshold, after a predefined amount of stimulation, ormaintains a level above a predefined threshold and, accordingly,automatically modifies the stimulation parameters, within a preset rangeof operation, to yield an improvement in LES pressure levels orfunction.

In one embodiment, a stimulator determines the LES pressure levelsremain above a predefined threshold level for a sufficient amount oftime such that a subsequent pre-programmed stimulation session orsessions can be postponed or cancelled. In one embodiment, a stimulatordevice monitors LES pressure and initiates stimulation only when LESpressure falls below a predetermined threshold. Preprogrammedstimulation may be modified in order to continue or increase in energy,duration, or frequency until LES pressure rises above a predeterminedthreshold. The LES pressure threshold may be dynamically modified basedupon sensed data.

In one embodiment, a stimulator determines that esophageal pH isindicative of incidents of acid reflux above a predefined thresholdlevel, and, accordingly, automatically modifies the stimulationparameters, within a preset range of operation, to yield an improvementin LES pressure increase to lower such incidents. In one embodiment, astimulator receives a communication from an external patient controlleddevice indicating that the patient is reporting a number of adverseincidents above a predefined threshold, such as acid reflux, generalizedpain, pain while swallowing, generalized discomfort, discomfort whileswallowing, lack of comfort when sleeping, etc. and, accordingly,automatically modifies the stimulation parameters, within a preset rangeof operation, to yield a lower level of such incidents. In oneembodiment, a stimulator receives a communication from an externalpatient controlled device detailing a schedule of potentially tLESRtriggering events, including sleep times, eating times, or exercisetimes, and, accordingly, automatically modifies the stimulationparameters, within a preset range of operation, to properly account forsuch tLESR triggering events.

In one embodiment, the stimulator operates using both open loop andclosed loop programming. Stimulation parameters may be established usingopen loop programming methods, as described above, and then modifiedthrough the aforementioned closed loop programming methods. Stimulationparameters may also be established using closed loop programmingmethods, as described above, and then modified through theaforementioned open loop programming methods.

Stimulation Modification Based on Sensed Data

It should be appreciated that the stimulation device may stimulate basedon a plurality of data, including based on LES pressure registeringbelow a predefined threshold, based on a patient's pH level, based onthe patient's physical orientation, based on the patient's meal intake,or based on a predefined time period, among other triggers. It shouldalso be appreciated that the controller may initiate or stop astimulation based on a plurality of triggers, including based on the LESpressure exceeding a predefined threshold, based on a patient's pHlevel, based on the patient's physical orientation, or based on apredefined time period, among other triggers.

Using various data sensors, including, but not limited to impedance,electrical activity, piezoelectric, pH, accelerometer, inclinometer,ultrasound-based sensors, RF-based sensors, or strain gauge, thestimulator device can determine whether a patient is eating, how muchthe patient is eating, how long the patient is eating, and/or what thepatient is eating, and, based on that information, adjust stimulationparameters accordingly. In particular, pH data may be used to determinewhat kind of food a patient is eating, where the type of food is definedin terms of its acidity.

In one embodiment, the stimulator device senses LES pressure andinitiates stimulation of the LES when the pressure is below apre-defined threshold level for a predefined period of time andterminates stimulation of the LES when the pressure is above apre-defined threshold level for a predefined period of time. LESpressure may be determined by sensing and processing impedancemeasurements, electrical activity measurements, strain gauge, and/orpiezoelectric measurements. One or more of the various measurements areconstantly measured to create a contiguous LES pressure profile. Basedupon the LES pressure profile, the stimulator can modify stimulationparameters, including pulse amplitude, pulse width, duty cycle, pulsefrequency, stimulation initiation time, ramp rate, or stimulationtermination time, to achieve, with respect to the LES pressure, anabsolute amount of change, a percentage amount of change, increases ordecreases above or below a threshold value, increases or decreases basedon time, increases or decreases based on a LES pressure slope, amongother measures of change.

In another embodiment, the stimulator device uses various data sensorsto determine the pulmonary, intra-thoracic, or intra-abdominal pressureand, based on pulmonary, intra-thoracic, or intra-abdominal pressure,create a patient-specific dose, such as a specific pulse amplitude,pulse width, duty cycle, pulse frequency, stimulation initiation time,ramp rate, or stimulation termination time, required to affect LES tone,pressure, or function to the levels needed by that patient.

In another embodiment, the stimulator device uses various data sensorsto determine the esophageal temperature and, based on that temperaturereading, create a patient-specific dose, such as a specific pulseamplitude, pulse width, duty cycle, pulse frequency, stimulationinitiation time, ramp rate, or stimulation termination time.

In another embodiment, the stimulator device uses various data sensorsto determine the esophageal pH and, based on that pH reading, create apatient-specific dose, such as a specific pulse amplitude, pulse width,duty cycle, pulse frequency, stimulation initiation time, ramp rate, orstimulation termination time.

In another embodiment, the stimulator device uses a combination of datainputs from the above described sensors to generate a total score fromwhich a stimulation therapeutic regimen is derived. For example, if thepatient has not eaten for a long time and lays down, a lower (or no)therapy dose would be delivered. Since tLESR is an episodic disease andcertain periods are more vulnerable to a reflux event than others,detecting various patient parameters by various means and using them inan algorithm enables clinicians to target those specific reflux events.In addition, in various embodiments, multiple algorithms are programmedinto the stimulator device so that treatment can be tailored to varioustypes of tLESR, based upon input relayed by the sensors. In oneembodiment, data from any combination of one or more of the followingparameters is used by an algorithm to determine stimulation protocol:patient feed state including type of intake (via patient input or eatingdetection by a physical sensor that can detect and/or evaluateliquids/solids/caloric value); patient position (viainclinometer/accelerometer); patient activity (viaaccelerometer/actimeter); patient reflux profile (via patient input/pHrecording); LES pressure; LES electrical activity; LES mechanicalactivity (via accelerometer in the LES, pressure sensor, impedancemeasure or change thereof); gastric pressure; gastric electricalactivity; gastric chemical activity; gastric temperature; gastricmechanical activity (via an accelerometer in the stomach, pressuresensor, impedance measurement and changes); patient intuition; vagalneural activity; and, splanchnic neural activity. Based on input fromone or more of the above parameters, the algorithm quantifies thevulnerability for a reflux event and modifies accordingly the amplitude,frequency, pulse-width, duty cycle, ramp rate, and timing of stimulationtreatment. The table below lists the parameters, measurements, andvalues used in an exemplary treatment protocol of one embodiment of thepresent invention.

TABLE 3 Parameter Measurement Value LES Pressure Normal 0 Low 1Inclination Upright 0 Supine 1 Feed State Fasting/Pre- 0 prandialPost-prandial 1 Time of the day Day time 0 Night time 1 Fat content ofmeal Low 0 High 1 Patient pH Profile Low-risk period 0 High-risk period1 Patient Symptom Low-risk period 0 Input High-risk period 1 GastricActivity Food Absent 0 Food Present 1 Upright Activity Low 0 Level High1 Supine Activity Level High 0 Low 1 Patient Intuition Low Likelihood 0High Likelihood 1

In the table above, each individual parameter is given a score of 1 or 0depending on the value measured. In one embodiment, a summary score istabulated using one or more parameters in the above exemplary algorithmscoring system to determine patient vulnerability to a reflux event.Based on the score, the treatment parameter is modified. Patients with ahigher summary score are indicated for a greater level of treatment. Forexample, a patient with normal LES pressure in the upright position anda pre-prandial state will be at minimal risk for a reflux event and notherapy will be indicated. Conversely, a patient with low LES pressurein the supine position and an immediate post-prandial state will be atthe highest risk for a reflux event and would receive the highest levelof tLESR therapy.

In one embodiment, a measured parameter is used as a modifier foranother parameter. For example, gastric activity showing food absentdoes not have an individual score but modifies the feed state score froma post-prandial score to a fasting/pre-prandial score. In anotherembodiment, a measured parameter has an absolute value that is notimpacted by other measured parameters. For example, patient intuition ofa high likelihood of a reflux event is an absolute parameter thatdelivers the highest level of tLESR therapy irrespective of other sensedparameters.

In one embodiment, the scoring system for certain individual parametersis a scale rather than a binary score. For example, in one embodiment,the score given to LES pressure is within a range from 0-5 based onduration of low pressure. With each incremental 5 minute duration of lowLES pressure, the score increases by one increment.

In another embodiment, different weight is given to differentparameters. For example, in one embodiment, low LES pressure is given anabsolute score higher than post-prandial feed state.

In another embodiment, the scoring system is tailored to be patientspecific. In one embodiment, for example, for a patient with low symptompredictability as ascertained by symptom association with a standard pHtest, patient symptom input is given a lower weight. In anotherembodiment, for a patient with mostly upright reflux on pH testing, theupright position is given a greater weight than the supine position. Inyet another embodiment, for a patient with exercise induced reflux, agreater weight is given to upright activity while the same parameterreceives a low weight or is eliminated from the algorithm in a patientwithout exercise induced reflux.

Accelerometer/Inclinometer Based Stimulation System

In one embodiment, the implantable device includes an accelerometer orinclinometer and a pre-programmed supine stimulation mode intended toautomatically provide the patient with additional stimulation sessionsduring extended time periods in which the patient is in the supineposition, as noted by said accelerometer/inclinometer. When the mode isenabled by a programmer, a supine position detection triggers additionalstimulation sessions based on pre-set programmable conditions. In oneembodiment, additional stimulation sessions will be initiatedautomatically when the following two conditions are met: 1) the patientis supine (based on a programmable range of inclination) for a minimumamount of time (based on pre-set time ranges) and 2) no stimulation wasapplied recently (maximal time programmable).

In one embodiment, the supine stimulation mode can be enabled ordisabled by the user via a programmer interface. The supine stimulationmode is available when the implantable device is in “cyclic” and “dose”modes, but not available (grayed out) when the device is in “continuous”and “off” modes. In another embodiment, the supine stimulation mode canbe implemented in conjunction with other stimulation modes, as describedabove, be the only mode of stimulation, or be disabled. In addition,when active, the supine stimulation mode may or may not overrideregularly scheduled stimulations or manually applied stimulations,depending on the programming. Further, when active, the supinestimulation mode may or may not deliver the same stimulation therapyprofile as programmed in the “cyclic”, “dose”, or other modes, asapplicable, depending on the programming.

In one embodiment, when the supine stimulation mode is enabled, anadditional set of specific programmable parameters becomes active on theprogrammer interface. This set includes the following parameters: supinetime; supine time percentage; supine refractory time; supine level;supine retrigger time and, supine cancel.

Supine time defines the period of time that is required for the patientto be in a supine position in order for the first condition listed aboveto be met. Supine time is programmable to a certain time period by theuser. In one embodiment, supine time is set to 1 minute. In anotherembodiment, supine time is set to 5 minutes. In another embodiment,supine time is set to 30 minutes. In yet another embodiment, supine timeis set to 60 minutes, or smaller increments thereof.

Supine time percentage defines the minimum percentage of data pointsrequired during the supine time in order for the first condition listedabove to be met. Supine time percentage is programmable to a certainpercentage by the user. In one embodiment, supine time percentage is setto 50 percent. In another embodiment, supine time percentage is set to70 percent. In another embodiment, supine time percentage is set to 90percent, or smaller increments thereof.

Supine refractory time defines the minimal amount of time required tohave passed from the end of the last stimulation session (scheduled,manual, or supine stimulation) before a new stimulation session may beinitiated via the supine stimulation mode. Supine refractory time isprogrammable to a certain time period by the user. In one embodiment,supine refractory time is set to 30 minutes. In another embodiment,supine refractory time is set to 60 minutes. In another embodiment,supine refractory time is set to 120 minutes. In yet another embodiment,supine refractory time is set to 180 minutes. FIG. 9 is an illustrationof a timeline 900 depicting a stimulation session 905 followed by asupine refractory time period 910. The supine refractory time period 910begins immediately after the end of the stimulation session 905 andcontinues through its pre-programmed duration. No additional stimulationinitiated by the supine stimulation mode can begin until the supinerefractory time period 910 has ended.

Supine level defines the level of inclination required to achieve asupine posture. Supine level is programmable to a range of degrees bythe user. In one embodiment, where the supine level is measured relativeto a horizontal body, supine level is set between 170 and 200 degrees.In another embodiment, supine level is set between 160 and 200 degrees.In another embodiment, supine level is set between 150 and 200 degrees.In yet another embodiment, supine level is set between 140 and 200degrees. In another embodiment, where the supine level is measuredrelative to a vertical baseline, supine level is set to an angle of 50,60, 70, or 80 degrees, where 0 degrees is a vertical position and 90degrees is a horizontal position.

Supine cancel defines the maximum amount of time that can elapse betweenthe end of a stimulation therapy session triggered by supine stimulationmode and the start of a regularly scheduled stimulation therapy sessionthat will cancel the regularly scheduled stimulation therapy session.Supine cancel is programmable to a certain time period by the user. Inone embodiment, supine cancel is set to 30 minutes. In anotherembodiment, supine cancel is set to 60 minutes. In another embodiment,supine cancel is set to 120 minutes. In yet another embodiment, supinecancel is set to 240 minutes. FIG. 10 is an illustration of a timeline1000 depicting a stimulation session 1005 triggered by supinestimulation mode followed by a supine cancel period 1010. The supinecancel period 1010 begins immediately after the end of the supinestimulation mode stimulation session 1005 and continues through itspre-programmed duration. Any regularly scheduled stimulation sessionscheduled during the supine cancel period 1010 will not be initiated.

Supine retrigger defines the maximum amount of time that may elapsebetween the end of a stimulation therapy session triggered by supinestimulation mode and the initiation of another stimulation. In oneembodiment, the supine retrigger period is programmable and may have avalue of 2 4, 6, or 8 hours, or any increment therein. In anotherembodiment, after a predefined threshold, such as 75%, of a supineretrigger period has passed, the stimulator initiates a post-sleepingstimulation, in anticipation of a breakfast meal event, if a verticalposition is sensed. In another embodiment, the stimulator does notinitiate a post-sleeping stimulation if a vertical position is sensed ifless than a predefined threshold, such as 75%, of a supine retriggerperiod has passed. It should be appreciated that an automatically setpost-sleeping stimulation is optional and that stimulation may simply bepreset for a particular time of the day.

Modifications to Prevent Habituation or Fatigue

Stimulation parameters may also be periodically modified, in accordancewith a predefined schedule or dynamically by real-time physician orpatient control, to reduce, avoid, or prevent the occurrence of musclefatigue, habituation, and/or tolerance. Manipulation of the length ofthe “on” and “off” cycles can be performed while still obtaining thedesired level of LES function. In one embodiment, the length ofstimulation time to achieve the therapeutic goal can be decreased whilethe stimulation off time required for LES function to return to baselinecan be increased. Less time spent in the “on” cycle will result in fewerincidents of muscle fatigue.

In another embodiment, the “on” and “off” cycles, as describedpreviously, can cycle rapidly. For example, during a 30 minute period,the stimulation may be on for 3 seconds and off for 2 seconds during theentire 30 minute period.

In another embodiment, the patient can take a “stimulation holiday”. Inother words, stimulation can be further stopped for a time periodgreater than the “off” cycle to allow the muscle to recover. Greatlyincreasing the time period in which there is no stimulation also servesto avoid muscle fatigue and tolerance.

In another embodiment, stimulation parameters can be intermixed in anattempt to avoid muscle fatigue, habituation, and/or tolerance whilestill obtaining the desired level of LES function. For example,alternating short pulses can be intermixed with intermediate pulses tostimulate the LES. The variation in stimuli received by the muscle willassist in avoiding fatigue and tolerance.

In another embodiment, LES function can be normalized using the presentinvention without raising LES pressure above the mid-normal range. Thisis achieved by minimizing the energy delivered to the muscle to, but notbeyond, the point where the LES regains normal function. Less energydelivered results in less fatigue and tolerance.

In another embodiment, the stimulation parameters can be changed, suchas by modifying pulse width, frequency, amplitude, ramp rate, or theduty cycle, on a predefined periodic basis to avoid having the muscleshabituate to a known and repeated stimulation setting. In such anembodiment, a stimulator may locally store a plurality of differentstimulation parameters which are implemented in accordance with apredefined schedule. The stimulator may also store a single set ofstimulation parameters, each parameter having an acceptable range ofoperation, and then randomly implement a stimulation parameter boundedby the acceptable ranges of operation.

Electrode Configurations and Methods of Placing and Confirming thePlacement of Electrodes

In one embodiment, the therapeutic objectives described herein areachieved by at least one of a plurality of different electrodeconfigurations, as shown in FIG. 11. It should be appreciated that, inone embodiment, the electrode placement, as shown, at least partlyenables the patient's LES function to normalize, post-stimulation,and/or the patient's LES pressure to increase post-stimulation. Theelectrode configurations described herein may be used in accordance withany of the stimulation parameters, system architectures, and sensingsystems described herein.

Within the esophagus 1100, and more particularly the LES, a plurality ofdifferent electrode combinations can be used to achieve the therapeuticand operational objectives described herein. In one embodiment, a firstelectrode 1105 is placed proximate to the left lateral wall of theesophagus 1100 and operated in combination with a second electrodeplaced proximate to the right lateral wall 1110 of the esophagus 1100.In one embodiment, a first electrode 1105 is placed proximate to theleft lateral wall of the esophagus 1100 and operated in combination witha second electrode placed in the anterior proximal wall 1115 of theesophagus 1100. In one embodiment, a first electrode 1110 is placedproximate to the right lateral wall of the esophagus 1100 and operatedin combination with a second electrode placed in the anterior proximalwall 1115 of the esophagus 1100. In another embodiment, a firstelectrode 1105 is placed proximate to the left lateral wall of theesophagus 1100 and operated in combination with a second electrodeplaced in the anterior, distal wall 1120 of the esophagus 1100. In oneembodiment, a first electrode 1110 is placed proximate to the rightlateral wall of the esophagus 1100 and operated in combination with asecond electrode placed in the anterior, distal wall 1120 of theesophagus 1100. In another embodiment, a first electrode 1115 and asecond electrode 1120 are placed proximally and distally in the anteriorwall of the esophagus 1100. In another embodiment, more than one of theabove described combinations are used serially along the length of theesophagus 1100.

Referring to FIG. 12, the electrodes 1205, 1210, 1215, 1220 can beplaced longitudinally or transversely or in any orientation relative tothe length of the esophagus 1200 and can be implemented in the sameexemplary combinations described in relation to FIG. 11. It should beappreciated that not all of the electrodes shown in FIG. 11 need to beimplanted or operated concurrently. For example, to achieve any of theaforementioned therapeutic objectives, only one pair of electrodes, suchas 1105 and 1110 or 1115 and 1120 need be implanted and/or operatedconcurrently.

In another embodiment, shown in FIG. 13, electrodes can be implanted inseries with two electrodes 1310, 1305 proximate to the left lateral wallof the esophagus 1300 and two electrodes 1315, 1320 proximate to theright lateral wall of the esophagus 1300. These electrodes can beactivated in various combinations, as described above, to provide forthe optimal normalization of LES pressure, with minimal energy deliveredto the tissue and minimal muscle fatigue or depletion ofneurotransmitter storages. It should be appreciated that stimulationparameters (amplitude, timing of stimulation session and switching ofelectrode configuration) will be set so as to activate release ofappropriate neurotransmitter. Such parameters can vary between patientsdue to surgical variation and physiological sensitivity. The electrodeactivation or implantation combinations can include electrodes 1310 and1315, electrodes 1310 and 1305, electrodes 1315 or 1320, electrodes1310/1315 alternating with 1305/1320, and electrodes 1310/1305alternating with 1315/1320.

It should be appreciated that the length and surface area of theelectrode and the distance between the electrodes can affect the degreeand duration of the patient's post-stimulation normalization of LESfunction. It should further be appreciated that the length and surfacearea of the electrode can affect the current amplitude required toincrease LES pressure post-stimulation.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting the electrodes in a“linear” configuration. This is accomplished by implanting a firstelectrode axially along the length of the smooth muscle of the LES,shown as 1115 in FIG. 11, and implanting a second electrode 1120 belowand substantially in alignment with the first electrode 1115. The bottomof the first electrode 1115 is separated from the top of the secondelectrode 1120 by a distance of no greater than 5 cm, preferably nogreater than 2 cm, and most preferably approximately 1 cm. Eachelectrode is placed preferably more than 1 mm away from the vagal trunk.This electrode configuration is supplied a stimulation pulse from astimulator. The stimulation pulse may be delivered in accordance withany of the aforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec and a pulse repetitionfrequency of 20 Hz. A stimulator may further be configured to detect anyof the aforementioned biological parameters, including LES pressure. Inone embodiment, the LES pressure is derived from a sensor adapted togenerate an impedance measurement. In one embodiment, LES pressure isderived from piezoelectric sensors or electrical activity based sensors.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting the electrodes in a“parallel” configuration. This is accomplished by implanting a firstelectrode axially along the length of the smooth muscle of the LES,shown as 1105 in FIG. 11, and implanting a second electrode 1110 axiallyon the other side of the esophagus 1100, parallel to the first electrode1105. The distance between the first electrode 1105 and the secondelectrode 1110 is less than half the circumference of the LES. Theelectrodes 1105, 1110 are implanted in the anterior of the LES, withpreferably at least one electrode being in the right anterior (thisplaces the stimulation as far as possible from the heart). Eachelectrode is placed preferably more than 1 mm away from the vagal trunk.This electrode configuration is supplied a stimulation pulse from astimulator. The stimulation pulse may be delivered in accordance withany of the aforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec. A stimulator mayfurther be configured to detect any of the aforementioned biologicalparameters, including LES pressure. In one embodiment, the LES pressureis derived from a sensor adapted to generate an impedance measurement.In one embodiment, LES pressure is derived from piezoelectric sensors orelectrical activity based sensors.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting a first electrodetransaxially across the length of the smooth muscle of the LES, shown as1215 in FIG. 12, and implanting a second electrode 1220 substantiallyparallel to the first electrode and spaced apart from the firstelectrode 1215 a distance of no greater than 5 cm. This electrodeconfiguration is supplied a stimulation pulse from a stimulator. Thestimulation pulse may be delivered in accordance with any of theaforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec. A stimulator mayfurther be configured to detect any of the aforementioned biologicalparameters, including LES pressure. In one embodiment, the LES pressureis derived from a sensor adapted to generate an impedance measurement.In one embodiment, LES pressure is derived from piezoelectric sensors orelectrical activity based sensors.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting a first electrodeand a second electrode in a configuration that concentrates currentdensity at two or fewer points close to each electrode. This electrodeconfiguration is supplied a stimulation pulse from a stimulator. Thestimulation pulse may be delivered in accordance with any of theaforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting a first electrodeand a second electrode in a configuration that avoids distributingsubstantially all of the current density along the lengths of eachelectrode. This electrode configuration is supplied a stimulation pulsefrom a stimulator. The stimulation pulse may be delivered in accordancewith any of the aforementioned stimulation parameters. In oneembodiment, the stimulation pulse has a pulse amplitude no greater than15 mAmp and more preferably no greater than 8 mAmp. In one embodiment,the stimulation pulse has a pulse width of approximately 200 μsec.

Variations in the stimulation and placement of electrodes also conveythe added benefit of avoiding muscle fatigue and tolerance, aspreviously discussed. For example, as shown in FIG. 12, two pairs ofelectrodes, 1205/1210 and 1215/1220, can be implanted and stimulated inalternative succession. In one embodiment, the two pairs of electrodesreceive simultaneous stimulations with the same stimulation parameters.In another embodiment, the two pairs of electrodes receive sequentialstimulations with the same stimulation parameters. In anotherembodiment, the two pairs of electrodes receive simultaneousstimulations with different stimulation parameters. In anotherembodiment, the two pairs of electrodes receive sequential stimulationswith different stimulation patterns. Electrode placement can also bemanipulated to decrease muscle fatigue and tolerance. In one embodiment,the two pairs of electrodes are placed so that the distance between anyset of electrodes is less than 2× the distance between the pair ofelectrodes, resulting in the stimulation from a set of electrodesstimulating less than 100% of the LES.

Preferably, during the implantation process, electrode configurationsare tested to verify that the proper configuration has been achieved. Inone embodiment, a catheter or endoscope configured to measure LESpressure in combination with a manometer is proximate to theimplantation area while the newly implanted electrodes are stimulated.LES pressure is measured before, during, and/or after stimulation. Ifthe desired LES pressure profile is achieved, the implantation is deemedsuccessful and the testing may terminate. If the desired LES pressureprofile is not achieved, the electrode configuration may be modified.LES pressure testing is then repeated until the proper LES pressureprofile is achieved. Other sensed data, such as temperature, may also beused in this testing process. It should be appreciated that the testingprocess can be conducted separate from the implantation procedure. Forexample, patients can be tested with temporary electrodes, insertednon-invasively (nasogastric, for example), and upon success can bedeemed suitable for implant.

Stimulator Energy Storage and Sensing Systems

Non-Sensing Active Implantable Medical Devices

The embodiments disclosed herein achieve one or more of the above listedtherapeutic objectives using stimulation systems that are energyefficient and do not require sensing systems to identify wet swallows,bolus propagation, or patient symptom changes, thereby enabling a lesscomplex, smaller stimulation device which can more readily be implantedusing endoscopic, laparoscopic or stereotactic techniques. The disclosedstimulation methods permit a natural wet or bolus swallow to overridethe electrically induced stimulation effect, thereby allowing for anatural wet or bolus swallow without having to change, terminate, ormodify the stimulation parameters.

It should be appreciated that, in one embodiment, the stimulation devicereceives energy from a remote energy source that is wirelesslytransmitting ultrasound or RF based energy to the stimulation device,which comprises receivers capable of receiving the energy and directingthe energy toward stimulating one or more electrodes. It should furtherbe appreciated that the device may be voltage driven or current driven,depending upon the chosen embodiment.

It should be appreciated that, in another embodiment, the stimulationdevice is a macrostimulator that receives energy from a local energysource, such as a battery, and directs the energy toward stimulating oneor more electrodes. It should further be appreciated that the device maybe voltage driven or current driven, depending upon the chosenembodiment.

By not requiring sensing systems that identify wet swallows, boluspropagation, or patient symptom changes, at least certain embodimentscan operate with increased reliability and also be smaller in size. Thesmaller device size results in increased patient comfort, allows forplacement (implantation) in the patient in more appropriate and/orconvenient locations in the patient's anatomy, and allows the use ofdifferent surgical techniques for implantation (laparoscopic,endoscopic) and/or smaller incisions, which are less invasive, causeless trauma, cause less tissue damage, and have less risk of infection.The small size can also allow placement of a larger number of devices soas to provide redundancy, improved clinical efficacy, durability andreliability.

In addition to the absence of certain components which, conventionally,were required to be part of such an electrical stimulation system,embodiments of the present invention can achieve the above-listedtherapeutic objectives using stimulation systems that operate at lowenergy level, such as at or below 20 Hz with a current of at or below 8mAmp, preferably 3 mAmp, and a pulse width of 200 μsec.

As a result of the operative energy range, the following benefits can beachieved: a) a wider range of electrode designs, styles, or materialsmay be implemented, b) the need to use special protective coatings onelectrodes, such as iridium oxide, or titanium nitride, while stillmaintaining electrode surface areas below 5 mm², is eliminated, c) onehas the option of using small electrode surface areas, preferably belowa predefined size with coatings to increase the effective surface area,such as iridium oxide, or titanium nitride, d) one can operate inwireless energy ranges that are within regulatory guidelines and safetylimits and do not pose interference issues, such as a RF field strengthbelow a predefined limit and ultrasound field strength below apredefined limit.

It should further be appreciated that the presently disclosed systemscan be implemented using a variety of surgical techniques, includinglaparoscopic and endoscopic techniques. In one embodiment, alaparoscopically implanted device comprises a battery providing localenergy storage and only optionally receives energy through wirelesstransfer, such as RF or ultrasound. In such an embodiment, the devicestimulates at a higher amperage for shorter periods of time, relative toembodiments without local energy storage, thereby allowing for longeroff cycles, lower duty cycles, and better battery efficiency. In oneembodiment, an endoscopically implanted device may or may not comprise alocal energy storage device but does comprise a wireless receiver toreceive energy wirelessly transmitted from an external energy source andtransmission device. In such an embodiment, this device stimulates at alower energy setting for longer on cycles and shorter off cycles,relative to the embodiment with local energy storage, thereby having agreater duty cycle than a laparoscopic implant.

The stimulators of the present invention, when properly programmed inaccordance with the stimulation parameters described herein andassociated with the appropriate electrode configurations, exhibit a highdegree of energy efficiency. In one embodiment, the electricalstimulation device initiates electrical stimulation based upon aninternal clock or a patient activated trigger. Electrical stimulationthen continues for a pre-set or predefined period of time. Referencing a24 hour period of time, the preset or predefined period of time may beequal to an “on” time period that is less than or equal to 24 hours, 12hours, 1 second, or any increment therein. Upon completion of thatpredefined period of time, the internal clock then causes the electricalstimulation device to terminate electrical stimulation.

It should be appreciated that any activation by an internal clock can beconfigured to cycle daily or a few times daily or be synchronized tomeal times, as signaled manually by a patient. It should further beappreciated that the timing of meal times or other physiologicallyrelevant events can be saved and/or learned, thereby enabling the deviceto default to standard initiation of stimulation time or termination ofstimulation time based upon past data gathered. The setting ofstimulation times may be set by a physician, based on an interview witha patient or based on the detection of eating using pH sensing or someother automated eating detection mechanism. In one embodiment,stimulation is initiated in advance of a predefined meal time to achievean increase in LES tone before the patient eats. For example, if apatient's predefined meal time is 2 pm, then stimulation is set toinitiate in advance of 2 pm, such as 1:30 pm. If the patient thenreports symptoms between 4-6 pm, then, in the future, stimulation may bereinitiated at 3 pm. If a patient's predefined meal time is 12 pm, thenset stimulation is set to initiate in advance of 12 pm, such as 11:30am. If the patient then reports symptoms between 2-4 pm, stimulation maybe reinitiated at 1 pm.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. Upon completion of that predefined periodof time, the internal clock then causes the electrical stimulationdevice to terminate electrical stimulation. This ratio of the predefinedperiod of stimulation relative to the time where electrical stimulationis terminated is less than 100%, up to a maximum duty cycle, such as70%, 75%, 80%, 85%, 90%, 95%, or any increment therein.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is up to a maximum “on” period, suchas 12 hours, during which the device may be continually operating. Uponcompletion of that predefined period of time, the internal clock thencauses the electrical stimulation device to terminate electricalstimulation.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is up to a maximum “off” period, suchas 12 hours, during which the device is not operating. Upon completionof that predefined period of time, the internal clock then causes theelectrical stimulation device to restart electrical stimulation.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is less than the time required to seea visible change in the LES pressure. Upon completion of that predefinedperiod of time, the internal clock then causes the electricalstimulation device to terminate electrical stimulation. The desiredincrease in LES pressure occurs post-stimulation, followed by a decreasein LES pressure which still remains above a pre-stimulation state aftera period of >1 hour.

It should be appreciated that other stimulation protocols, which resultin the desired effect of operating for less than 100% of duty cycle andwhich have a pre-set or predefined period of non-stimulation, can beachieved using combinations of turning on and off subsets of electrodesat different times. For example, one may turn a first subset ofelectrodes on, turn a second subset of electrodes on, then turn allelectrodes off, followed by turning a second subset of electrodes on,turning a first subset of electrodes on, and then all electrodes offagain.

Sensing Active Implantable Medical Devices

It should be appreciated that the present invention can be optionallyoperated in combination with sensing systems capable of sensingphysiological events, such as eating, swallowing, a bolus propagatingthrough the esophagus, muscle fatigue, pH level, esophageal pressure,tissue impedance, LES tone/pressure, patient position, sleep state, orawake state. In such a case, a physiological event can be used to modifythe stimulation schedule by, for example, extending the stimulation timeperiod based upon sensed pH level, eating, swallowing, or a boluspropagating through the esophagus or, for example, terminating thestimulation period before the preset time period expires based uponsensed muscle fatigue.

It should also be appreciated that the present invention can be drivenby, and fully triggered by, sensing systems capable of sensingphysiological events, such as eating, swallowing, a bolus propagatingthrough the esophagus, muscle fatigue, pH level, esophageal pressure,tissue impedance, LES tone/pressure, patient position, sleep state, orawake state. In such a case, a physiological event can be used toinitiate the stimulation schedule.

By operating the stimulation system less than 100% duty cycle and havingthe stimulation device be off during preselected periods, the presentlydisclosed stimulation system uses less energy than prior art devices.Accordingly, the stimulation systems disclosed herein can effectivelyoperate to achieve the above-listed therapeutic objectives using anenergy source local to the stimulator that a) does not include abattery, b) includes a small battery capable of being recharged from anexternal energy source, c) only includes a capacitor and, morespecifically, a capacitor having a rating of less than 0.1 Farads or d)only includes a battery that is not rechargeable.

In one embodiment, a stimulator uses a remote data sensor forautomatically adjusting parameters. The stimulator comprises stimulatingcircuitry contained within a housing that includes a power source, meansfor delivering stimulation, a receiver to collect data from a remotesensor and a control unit that analyzes the data received from thereceiver and adjusts the stimulation parameters based on a plurality ofstored programmatic instructions and the received data. The means forstimulation may include any form of leaded or a leadless device. Thestimulator element would preferably be implanted either under the skin,in cases where the stimulator comprises a macrostimulator internal pulsegenerator (IPG), or close to the stimulation area, in cases where thestimulator comprises a microstimulator. The stimulator can also comprisea plurality of separate units, in separate housings, including, forexample, an external control unit and receiver and an implantablestimulator, similar to a passive microstimulator.

The stimulator is in wireless or wired data communication with one ormore sensor elements. The sensor elements are implanted in an area thatallows the sensor to collect physiological data relevant to thecontrolling the operation of the stimulator. Each sensor elementincludes means for sensing the required physiological function and meansfor transmitting the data to the control unit. In one embodiment, thesensor element comprises a capsule adapted to measure physiological pHand transmit pH data from within the lumen of the esophagus to animplantable stimulator device. In another embodiment, the sensor elementcomprises a pH sensor located within a nasogastric tube and means fortransmitting the pH data to an implanted control unit. In anotherembodiment, the stimulator comprises electrodes implanted in the LESthat are wired to an implantable IPG, which is in data communicationwith a pH measuring element, such as but not limited to a pH capsule ora catheter based device, that is transmitting pH data to the device viauni-directional or bi-directional communication.

In another embodiment, the stimulator/sensing system disclosed hereincan locally store a plurality of programmatic instructions that, whenexecuted by circuitry within the IPG, uses data received from a capsuleto automatically refine stimulation parameters within a pre-definedrange of boundaries. The data may be continuously streamed from thesensing capsule to the IPG and may be subject to continuous monitoringand processing. The data may comprise any one of pH data, pressure data,LES pressure data, temperature, impedance, incline, or otherphysiological data.

Referring to FIG. 14, a patient 1400 has implanted within his tissue astimulator 1415, as further described below. The stimulator 1415 isadapted to dynamically communicate with a temporary sensor 1410, asfurther described below, which may be located inside the patient's GIlumen. The implanted stimulator 1415 comprises stimulator circuitry andmemory having programmatic instructions that, when executed, perform thefollowing functions: transmit an interrogating signal designed to elicitor cause a transmission of sensed data from the temporary sensor 1410 orreceive a transmitted signal comprising sensed data from the temporarysensor 1415 and process the sensed data to modify stimulationparameters, such as frequency, duration, amplitude, or timing.Optionally, the stimulator 1415 may also analyze the received senseddata signal to determine if the data is reliable. The implantedstimulator 1415 is adapted to only modify stimulation parameters orotherwise engage in a processing routine adapted to use the sensed datato determine how the simulation parameters should be modified when itsenses and receives the sensed data. Optionally, the implantedstimulator 1415 is adapted to modify stimulation parameters or otherwiseengage in a processing routine adapted to use the sensed data incombination with patient data inputted into an external device todetermine how the simulation parameters should be modified.

For example, where a meal event, sleeping event, or other event whichmay cause, be related to, or be associated with a tLESR event, isexpected to occur at a specific time during the day (either becausepreviously sensed data has determined a pattern indicating the existenceof such an event or because patient data expressly indicates that suchan event should be expected), stimulation parameters may be modified orotherwise established in order to provide the requisite level, degree oramount of stimulation before the anticipated event, such as 5 minutes,10 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes,or some increment therein. The determination of stimulation parameters,including start time, end time, pulse frequency, duration, ramp rate,duty cycle, and/or amplitude, can be determined independent of thepatient's immediate physiological state and not causally related to thepatient's existing condition. Rather, historical data patterns fromsensors, including pressure data, LES pressure data, temperature,impedance, incline, or other physiological data, can be used to definethe tLESR profile of a patient, namely when, in the course of a day, apatient is likely to experience a tLESR event, and then used toproactively normalize LES function in advance of the tLESR event. Toproperly generate and mine data patterns, it is preferable to captureboth the magnitude of the physiological data (i.e. pH<4), the duration(for one hour), and the timing (around 1 pm). It is further preferableto associate different physiological data with each other to see if apredictive pattern may exist between data sets and to further correlatethat data with the patient's own reporting of pain, discomfort, acidreflux, or other sensations to better determine when a tLESR event islikely to occur in a day.

In one embodiment, the implanted stimulator 1415 is configured to checkthe reliability of the data by processing it to determine whether thedata is indicative of the sensor being in an improper location. In oneembodiment where the temporary sensor is a capsule measuring pH dataintended to measure esophageal pH, such a determination process may beconducted by: a) monitoring the received pH data over a predefinedperiod of time to determine if it is indicative of a high pHenvironment, such as the patient's stomach as opposed to the esophagus,b) monitoring the received data signal, such as an RF signal, over apredefined period of time to determine if the signal strength hassignificantly changed or modified, indicating a change in physicallocation, or c) monitoring a received accelerometer or inclinometer datasignal from the pH capsule, over a predefined period of time, todetermine if the capsule is in a proper physical orientation. Dependingon the reliability check, the implanted stimulator 1415 may use, ordiscard, the sensed data. If no reliable data is received by theimplanted stimulator 1415, it does not modify stimulation parameters orotherwise engage in a processing routine adapted to use the sensed datato determine how the simulation parameters should be modified. Ifreliable data is received by the implanted stimulator 1415, it modifiesstimulation parameters or otherwise engages in a processing routineadapted to use the sensed data to determine how the simulationparameters should be modified.

The temporary sensor 1410 may store the sensed and transmitted data andtransmit the stored data to an external reading device. It should beappreciated that the previously discussed methods for using sensed data,whether from a temporary sensor or permanently implanted sensor, may beperformed by an external device. For example, an external device maywirelessly receive sensed data and use the sensed data to determine apattern indicative of when a tLESR event is likely to be experienced bya patient. Any pattern analysis method known to persons of ordinaryskill in the art may be used. The data may include some or all of thesense data, externally inputted patient data, or a combination thereof.As discussed above, the external device would use the data to determinethe time(s) of day when a patient typically experiences a tLESR eventand the appropriate stimulation parameters required to normalize LESfunction prior to such tLESR event. The requisite stimulation parametersmay be determined by examining historical tLESR events in relation tostimulation parameters that had been implemented and modifying thestimulation parameters to increase or decrease the magnitude or durationof the stimulation accordingly. Additionally or alternatively, theimplanted stimulator 1415 may store the sensed data and data indicativeof how stimulation parameters, such as frequency, duration, amplitude,or timing, were modified based on the sensed data, and transmit thestored data to an external reading device.

Referring to FIG. 15, in one embodiment, the process 1500 implemented bythe stimulator system comprises collecting 1505 pH data periodically orcontinuously over a predefined period, such as 1, 2, 6, 12, 24, 36, 48,or 60 hours, or any time increment in between. Circuitry within thestimulator analyzes the pH data 1510 to determine if, within thepredefined period, such as 24 hours, pH is less than a predefined value,such as 4, for a percentage of time higher than a threshold value, suchas 1, 2, 3, 4, 5, 10, 15, or 20 hours, or any increment therein 1515.The processor may analyze pH data 1510 by integrating periods in whichthe pH is less than the predefined value compared with stimulation timesand separately integrate periods with stimulation in a most recent timeperiod (i.e. last 6 hours) to periods without stimulation in the mostrecent time period.

If the percentage of time with the pH less than the predefined valuewithin a predefined period is lower than a threshold value, such as 1percent or lower 1520, then the circuitry may adjust stimulationparameters 1525 so as to reduce the timing, frequency, or size of thestimulation doses. In one embodiment, the circuitry decreases dailystimulations or amplitudes by a discrete amount, such as 1 mAmp. In oneembodiment, the system may not reduce the timing, frequency, or size ofthe stimulation doses below a minimum dose.

If the percentage of time with the pH less than the predefined valuewithin a predefined period is greater than a threshold value, such as 5percent or higher 1515, then the circuitry may further analyze 1530whether there were more periods with pH being greater than the thresholdvalue during which there was no stimulation than with stimulation. Ifthere were more periods with pH being greater than the threshold valueduring which there was no stimulation than with stimulation, thecircuitry may increase the number of daily stimulations by a discreteamount, such as by 1 1535 or the duty cycle or length of a givenstimulation session or duration by a discrete amount, such as 1 minute.By doing so, the system assumes the amount of energy delivered perstimulation is sufficient, but there simply were not enough stimulationevents in a day, or the stimulation was not long enough. If there weremore periods with pH being greater than the threshold value during whichthere was stimulation than with no stimulation, the circuitry increasesthe amplitudes of stimulations by a discrete amount, such as by 1 mAmp1540. By doing so, the system assumes the amount of energy delivered perstimulation was not sufficient and therefore increases the energydelivered per stimulation. In one embodiment, the system may notincrease the timing, frequency, or size of the stimulation doses above amaximum dose.

In general, if the percentage of time within a predefined period duringwhich pH is less than a threshold value, such as 4, is higher than anupper value, such as 5%, then the stimulation parameters will beadjusted so as to increase dose. Also, if the percentage of time withina predefined period during which pH is less than a threshold value, suchas 4, is lower than a lower value, such as 1%, then the stimulationparameters may be adjusted so as to reduce dose. The decreasing andincreasing of dose will be done based on the temporal behavior of the pHvalues. It should be appreciated that doses may be incremented by anyamount. It should further be appreciated that doses can be effectivelydecreased or increased by increasing one parameter while reducinganother parameter so that the total energy is increased, reduced, orunchanged. Finally, it should be appreciated that all modifiableparameters will be bounded, on at least one of the maximum or minimumboundary, by a range defined by a healthcare provider.

In another embodiment, the operation of the system is augmented withother sensed data. Where the system is being used to stimulate the LESor treat tLESR, pH sensor data can be augmented with accelerometerand/or inclinometer data. The accelerometer or inclinometer sensor(s)could be located within the implantable device or in another device onor inside the patient body. This additional data can enable the controlunit algorithm to assess patient modes (e.g., sleep, exercise, etc) andthereby to improve the tuning of stimulation parameters for a specificpatient, thereby improving device efficacy and/or efficiency. Additionalsources of information may include, but not be limited to, pressuremeasurement or an impedance measurement by a capsule or an eatingdetection mechanism using one or more sources such as impedance or otherelectrical or electromechanical measurement from within the tissue orfrom the lumen. These additional sources of information can further beused by the control unit to adjust the stimulation dose and otherparameters and other functions of the implantable device. It should beappreciated that any of the aforementioned data may be used individuallyor in combination to modify the operation of the system and, inparticular, to determine how stimulation parameters should be modifiedto address an anticipated patient tLESR event.

In another embodiment, the system logs the sensed and computed data anddownloads the data to an external device for viewing and analyzing by amedical professional or a technician. By permitting on-demand or batchdownloading, the system can eliminate the need for the patient to carryan external receiver during pH-sensing, thereby improving the useexperience of the patient and potentially improving compliance andallowing for longer measurement periods. The system can download dataautomatically and without any requirement for user intervention, such aswhen an appropriately calibrated external device comes within a datacommunication area of the implanted device, or semi-automatically, suchas when initiated by the implantable device when the implantable deviceis in proximity (communication distance) of the external device and theuser has provided a password or other indication of approval via theexternal wireless interrogation device.

It should be appreciated that the external device receiving the sensedor computed data could be located at the healthcare provider's locationor at the patient's home. If captured at the patient's home, the datacould be automatically sent to the clinic for physician review and/orapproval of suggested parameter changes via any communication medium,including Internet, Ethernet network, PSTN telephony, cellular,Bluetooth, 802.11, or other forms of wired or wireless communication.The transmitted data preferably contain the measured values, therecommended stimulation parameters adjustments, or both. Similarly, thephysician approval, or physician suggested parameter changes, could besent back to the external device located at the patient's home which, inturn, transmits appropriate commands to the implanted device, when thetwo devices are in proximity, to initiate the suggested parameterchanges.

In another embodiment, the system monitors sensor, such as capsule,failure. If the sensor fails an internal diagnostic test, a failure oralert signal is transmitted to the implanted control unit, or theimplanted control unit itself logs a failed attempt to communicate with,or obtain uncorrupted data from, the sensor. The control unit thentransmits that failure or alert signal data to the external device and,in turn, to the healthcare provider, as described above, therebyalerting a healthcare provider that the patient needs to return to havethe sensor fixed or another sensor implanted.

In another embodiment, the system is capable of recognizing andregistering a plurality of different sensing devices, such as capsules,and re-initiate newly implanted sensors as required to ensure continuousor substantially continuous measurement. For example, the stimulator canbe implanted for a long period of time, such as several months or years,and for a shorter period of time, such as once per annum, a sensor isimplanted. The stimulator registers the new sensor and automaticallyadjusts the new sensor for operation in the particular anatomicalregion, such as the esophagus.

In addition to failing, sensors may migrate out of the implantedanatomical region. For example, where a sensor, such as a capsule, hasbeen implanted into a patient's esophagus but has migrated to thestomach, the physical location of the sensor can be derived by examiningthe sensed data. For example, where a pH capsule has moved from theesophagus to the stomach, the capsule will likely transmit dataindicative of extensively long periods during which the pH is highlyacidic. In that case, the stimulator system can assume the capsule hasmigrated, report this failure to an external device, and ignore futuredata being transmitted from the capsule or record the data but not relyupon it for parameter setting. Similarly, the stimulation system mayregister a weaker or changed signal, indicative of a sensor moving adistance away from the recording device.

The presently disclosed stimulator system may further comprise areceiving antenna integrated into a stimulator system, which may be usedfor energy transfer to the stimulator system and communication to andfrom the device. The close proximity between the stimulator,particularly a miniature device, and a sensor, such as the pH capsule,can be used to achieve communication efficiency and increase durabilitythrough a miniature antenna in the stimulator that can accept data fromthe pH capsule. The close distance can effectively reduce powerrequirements and enables typical low frequency inductively coupledtelemetry for transmission through titanium via coils; as well as highfrequency RF communication such as MICS or IMS bands via monopole,dipole, or fractal electric field antennas. The communication distancecan be further reduced by enabling anchoring of the pH capsule ornasogastric tube to the implanted control unit. This can be facilitatedby, for example, a magnetic force between the two units caused by amagnet in both units or a magnet in one unit and a ferrous metal in theother.

One of ordinary skill in the art would appreciate that other means forcommunication can be used that will take advantage of the closeproximity between the stimulating electrodes and the sensing device,such as a pH capsule, even when the control unit is farther away,thereby allowing for a significant reduction in the power consumptionand improvement of reliability of communication. The stimulatingelectrodes in that embodiment would serve as receiving antennas and alsosimplify the design of the control unit, thereby avoiding the need for areceiving coil, antenna or other electromagnetic receiving means.

Bi-directional communication between the control unit and the sensorunit can be implemented as part of the system to allow, for example,calibration or activation of specific actions such as additionalmeasurements, determination of measurements to be taken, determinationof measurement times, local stimulation by the sensor unit, among othervariables. The sensor unit can also be used to not only transmit thesensed data, but also to transmit energy for charging and powering thecontrol unit and the stimulating device. For example, pH capsules thatfurther acts as an energy recharging source can be periodicallyimplanted, as required, to deliver energy to the control unit or amicro-stimulator in addition to actually sensing pH data.

Patient Selection Methods

In one embodiment, a person is permitted to practice the treatmentsystems and methods disclosed herein and, in particular, to have anembodiment of the electrical stimulation systems disclosed hereinimplanted into him or her only if the person passes a plurality ofscreening or filtering steps.

In one embodiment, a plurality of physiological measurements are takenof the patient and used to determine whether the patient maytherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein. LES pressure data and/or pH datais collected from the patient. For example, pH measurements are obtainedover a period of time, such as 4, 8, 12, 16, 20, or 24 hours or someincrement therein. The amount of time within the predefined measurementperiod during which the pH measurement is above a predefined thresholdindicative of acid exposure, such as a pH of 4, is calculated. Thenumber of acid exposure events occurring for more than a predefinedperiod of time, such as more than 1, 3, 10, 15, or 20 minutes, or anyincrement therein, is determined. The total time for each acid exposureevent lasting more than the predefined period of time, i.e. 3 minutes,referred to as a long event, is then summed. If that total time exceedsa predefined threshold, such as 5 minutes to 240 minutes or anyincrement therein, it may be concluded that the patient wouldtherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein. For example, if a patient has 4events of acid exposure lasting 1, 4, 5 and 6 minutes and the predefinedthreshold is 3 minutes, the total time would be equal to 15 minutes(4+5+6). If the total time threshold is 10 minutes, then the patient canbe categorized as an individual who would benefit from the electricalstimulation treatment systems and methods disclosed herein.

Another physiological measurement that may be used to select eligiblepatients is LES end expiratory pressure (LES-EEP). In one embodiment, apatient's LES-EEP is measured and collected during resting time, e.g. noswallow for at least 30 seconds, and then compared to at least onethreshold. For example, the value of the LES-EEP should be below anormal value threshold, such as 10-20 mmHg, preferably 12-18 mmHg, andmore preferably lSmmHg, in order for the patient to qualify fortreatment. In another embodiment, a patient's LES-EEP is measured andcollected during resting time, e.g. no swallow for at least 30 seconds,and then compared to a range of pressure values, e.g. to two differentthreshold values. For example, the value of the LES-EEP should be abovea lower threshold, which is indicative of the LES having some basefunctionality, such as 0 mmHg to 3 mmHg or any increment therein andbelow an upper threshold, such as 8 mmHg to 10 mmHg or any incrementtherein.

Another physiological measurement that may be used to select eligiblepatients is the rate of transient LES relaxation events (tLESr).Patients with higher rates of tLESrs which constitute a portion of theiracid exposure time above a predefined threshold may benefit less fromtreatment than patients with lower rates of tLESrs constituting aportion of their acid exposure time above a predefined threshold. In oneembodiment, a patient's tLESr rate is determined over a period of time,such as 24 hours or less. The tLESr rate is determined by recording thenumber and duration of acid exposure events, as described above, andthen calculating the number of acid exposure events shorter than apredefined time period, such as shorter a total time threshold, asdefined above, shorter than 5 minutes, shorter than 10 seconds orshorter than any increment therein, generally referred to as a shortevent. The number of such short events per period is then compared to aninclusion threshold, such as a range of 3-50, preferably 5-20. If thenumber of short events is below the range, the patient may not qualifyfor treatment or may qualify for a different stimulation regimen thatcan be programmed into the stimulator.

In another embodiment, a patient's acid exposure times are recorded andthen compared to the timing of patient's reported reflux symptoms. Thedegree of temporal correlation between the acid exposure times andreported symptoms is then determined. Patients with a degree ofcorrelation above a predefined threshold would be eligible for treatmentwhile those below the predefined threshold would not be.

In another embodiment, it is determined whether a patient maytherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein by temporarily stimulating thepatient for a period of time, such as less than one week, using anon-permanent implanted stimulator to evaluate the patient'sphysiological response to stimulation and predict the patient's likelyphysiological response to a permanent stimulator. In one embodiment, thetemporary stimulation is delivered using a temporary pacing leadendoscopically implanted in the patient's LES and connected to anexternal stimulator, which is either a non-portable system or a portablebattery-operated device. The temporary stimulation system deliversperiodic stimulations over a period of time, from 30 minutes to twoweeks or more, during which the patient's symptoms, acid exposureevents, and physiological response are recorded and correlations betweenthe three are determined. The temporary stimulation data can then beused to determine the likely timings of tLESR events and the requiredstimulation parameters to proactively normalize the patient's LES inadvance of the tLESR events, as previously discussed. Once the temporarystimulation period is complete, the electrode can be removed and adecision can be made regarding whether the patient would therapeuticallybenefit from a permanent implant based, for example, on the patient'sphysiological response to the temporary stimulation, improvement insymptoms, normalization of pH levels, and/or normalization of LESpressure.

In one embodiment, the temporary stimulator is in the shape of a smallcapsule-like device that is self-contained and includes all requiredcomponents for stimulation including a power source or a receiver thatallows power to be received wirelessly from outside the body and one ormore electrodes. The device is adapted to stimulate the LES tissue. Thedevice also includes an anchoring component, such as a hook, corkscrew,rivet, or any other such mechanism, which temporarily connects it to theLES wall. The capsule is implanted through an endoscopic orcatheterization procedure to the LES wall. Such a capsule is expected toremain attached to the LES wall for a period of one day to two weeks orlonger and then detach by itself and leave the body naturally. Furtherthe device can include a sensor for detecting when it is attached to thewall, which will only stimulate when it detects that the device is stillattached to the LES wall. Additionally the device may include wirelesscommunication to allow telemetry and/or commands to be delivered fromoutside the body. The capsule can additionally include pH measurement,manometry measurement or other physiological measurement devices orsensors so that the short term efficacy of the stimulation can be moreeasily evaluated. Additional standard measurements can be made as neededfor obtaining more information.

It should be appreciated that any form of temporary stimulator could beused. For example, a stimulator can include a) a plurality ofimplantable leads adapted to be temporarily implanted into the LEStissue through endoscopy, laparoscopy or other minimally invasivemethods and further adapted to deliver stimulation to the LES, b) ahousing which includes a control unit and circuitry for generatingelectrical stimulation where the housing is adapted to be temporarilyimplantable and/or be integrated with the leads such that the housingitself can deliver stimulation or externally located and wired to theleads without being implantable and/or c) an additional unit capable ofrecording the physiological data, stimulation data, and various patientinputs (symptoms, eating, sleeping events, etc.) and adapted to be usedfor turning stimulation on or off. Optionally, the additional unit iscontrolled by a physician and wirelessly programmable using aphysician's computer system. Optionally, the stimulator can also beconfigured to include sensors or communicate with sensors that measurethe aforementioned physiological measures.

Other approaches for selecting patients based on physiological dataand/or temporary stimulation can also be implemented. It should be clearto person skilled in the art that the above selection methods could beintegrated in various ways to result in an optimal selection ofpatients. For example one integrated method can be used to screenpatients by qualifying candidates according to pH long events, themanometry value of LES-EEP, or the number of short events, or anycombination thereof. Additionally, a combination of the measures can beused such as dividing the total length of long events by the rate ofshort events and comparing this value against a properly adjustedthreshold, such that patients with a ratio above the threshold areincluded and others are excluded. Once qualified, the patient canundergo the permanent implant procedure or undergo the temporarystimulation process to further qualify the patient.

Physician Diagnostic and Programming Systems and Methods

Different patients may require different therapeutic regimens, dependingupon implant depth, anatomical variations, treatment objectives, andseverity of the disease condition. Each patient has a different restinglower esophageal sphincter (LES) pressure and different responses tostimulation (due to expected variability in sphincter muscle conditionand also in the implant location). Furthermore, changes to the patient'sanatomy, for example arising from normal healing after implantation,chronic stimulation or age, can also change the optimal stimulationdosage. Accordingly, it is preferred for a patient to first undergo adiagnostic process to determine whether, and to what extent, the patientcan be treated by one of a plurality of therapeutic processes, asfurther described below. It is also preferred for a patient toperiodically visit a physician to have the efficacy of the stimulationsystem checked, optimized, and possibly reprogrammed, as provided below.

In one embodiment, because the goal is to keep the sphincter at apressure or function which eliminates or greatly reduces the chances foracid exposure, it is unnecessary for the muscle to always have highpressure but, rather, it is desirable to have (1) some average pressuresustained at all times with a certain permitted range of variabilityaround it and a minimal pressure that the sphincter will never be, orwill rarely be, below or (2) some average function sustained at alltimes with a certain permitted range of variability around it and aminimal function that the sphincter will never be, or will rarely be,below or a combination thereof. Continuous non-stop stimulation is notoptimal because the acute response of enhanced pressure may diminishover time due to neuro-muscular tolerance or muscle fatigue.Furthermore, a simple “on-off” regime during which the muscle isstimulated for a first duration and then the stimulation is turned offfor a second duration may be effective; however, different muscleproperties, variations in the patient condition, and variations in theimplant may require a different selection of the “on” and “off” periodsfor each patient and may also require a change in the initial selectionof the “on” and “off” periods over time in the same patient.

In one embodiment, a patient's average pressure (AP) and minimalpressure (MP) is set by conducting a parameter setting test, in which astimulator is controlled by an operator and a manometry measurement ofLES pressure is made. During this test, the operator turns on thestimulation and then observes the LES pressure while keeping thestimulation on until the pressure crosses a first threshold, defined,for example, by AP+(AP−MP). When the observed pressure passes this firstthreshold, the stimulation is either turned off or kept on for anadditional short period of up to 5 minutes and then turned off. Theoperator notes the time when the stimulation is turned off.

The operator continues to observe the pressure and once the pressurereaches MP, the operator turns on the stimulation again and notes thetime. This measurement process continues for several hours, such as 2 to5 hours, so that several stimulation on-off periods can be recorded. Atthe end of the test period, a chronic “on” time is selected to be themedian of the measured “on” periods and a chronic “off” period isselected to be the median of the measured “off” periods. It should beappreciated that the initiation of stimulation, turning off ofstimulation, recordation of time periods, and recordation of LESpressure can be performed automatically, based on a pre-programmed setof threshold values, by a computing device comprising a processor andmemory storing the threshold and control instructions as a set ofprogrammatic instructions.

In another embodiment, a patient's average pressure (AP) and minimalpressure (MP) is set by conducting a parameter setting test, in which astimulator is controlled by an operator and a manometry measurement ofLES pressure is made. During this test, the operator turns on thestimulation, notes the electrode impedance value, and then observes theLES pressure while keeping the stimulation on until the pressure crossesa first threshold, defined, for example, by AP+(AP−MP). When theobserved pressure passes this first threshold, the stimulation is eitherturned off or kept on for an additional short period of up to 5 minutesand then turned off. The operator notes the time when the stimulation isturned off and the electrode impedance value when the stimulation isturned off.

The operator continues to observe the pressure and once the pressurereaches MP, the operator turns on the stimulation again and notes thetime and electrode impedance value. This measurement process continuesfor several hours, such as 2 to 5 hours, so that several stimulationon-off periods can be recorded. Electrode impedance is measured everytime the stimulation is turned “on” or “off”. At the end of the testperiod, a chronic “on” time is selected to be the median of the measuredimpedance value for the “on” periods and a chronic “off” period isselected to be the median of the measured impedance value for the “off”periods. Rather than setting a stimulation device to operate based onfixed time periods, a stimulation device is programmed to turn off andon based upon the measured impedance values, where the device turns onwhen a patient's impedance value approaches the measured mean, median,or any other calculated impedance value for the on periods and turns offwhen a patient's impedance value approaches the measured median, mean,or any other calculated impedance value for the off periods. It shouldbe appreciated that the initiation of stimulation, turning off ofstimulation, recordation of time periods, recordation of electrodeimpedance, and recordation of LES pressure can be performedautomatically, based on a pre-programmed set of threshold values, by acomputing device comprising a processor and memory storing the thresholdand control instructions as a set of programmatic instructions. Itshould be appreciated that, in addition to the above embodiments, apatient's LES pressure may be recorded by conducting a parameter settingtest, in which a stimulator is controlled by an operator and a manometrymeasurement of LES pressure is made. The recorded LES pressures arecompared to a predefined threshold to determine a maximum pressure whichshould preferably not be exceeded. The aforementioned on and off periodsare then set or modified based on this maximum pressure data.

It should be appreciated that the use of impedance values is useful,relative to manometry measurements, if the values of the “on” and “off”periods in the acute phase do not converge to a small range within a fewminutes. It should further be appreciated that other measurements,instead of impedance, can be used, including physical tension sensors(i.e. implantable strain gauge) or sensors of the muscle electricalactivity or sensor of muscle pressure. Furthermore, it should beappreciated that both of the aforementioned tests can be used, and/orcombined, to fix time windows for the “on” and “off” periods and rely onimpedance measurements in order to adapt, modify, or change the timewindows to account for a possible drift in muscle status

In another embodiment, a doctor makes a determination regarding the LESelectrical stimulation therapy (LES-EST) available to a patient by firstengaging in a process for evaluating a plurality of appropriate dosingvalues for a patient. The evaluation process comprises subjecting apatient to a plurality of pulse sequences and measuring thecorresponding LES pressure.

TABLE 4 Electrical Pulse Pulse Phase # Stimulation Type FrequencyDuration Pulse Amplitude 1 Short Pulse 20 Hz 200 μsec 5 mAmp 2 ShortPulse 20 Hz 200 μsec 3 mAmp If #1 reaches ≧20 mmHg 3 Short Pulse 20 Hz200 μsec 7 mAmp If #1 does not reach ≧20 mmHg 4 Short Pulse 20 Hz 200μsec 10-15 mAmp If #3 does not reach ≧20 mmHg 5 Intermediate 20 Hz  3 ms3-15 mAmp using the same Pulse sequence as 1-4 6 Optimal Pulse 20 HzOptimal Optimal amplitude Pulse

As shown above, each of phases 1-4 is applied for 20-30 minutes with a20-30 minute interval between sessions. The pulse increments can rangefrom 0.1 mAmp to 15 mAmp. The pulse in Phase 6 is intermittently appliedfor 5 hours, during which stimulation is turned on until pressure isgreater than or equal to 20 mmHg for at least 5 minutes (on period) andthen turned off until pressure drops to less than 10 mmHg or patient'sbaseline whichever is higher (off period), and then turned on againuntil it is greater than or equal to 20 mmHg again (on period),repeating thereafter. These on-off sessions continue while the timedurations are recorded. These recorded periods are then used todetermine the optimal duty cycle for the patient during the treatmentphase (patient-specific LESEST). It should be appreciated that, if asubject experiences pain or discomfort for any given stimulationsequence, the pulse amplitude is decreased in 1 mAmp increments untilstimulation is tolerable. Once the effective tolerable setting isestablished, the patient-specific LES-EST is initiated with the definedstimulation parameters, as determined by the parameter setting stagedescribed above. Preferably, the patient-specific LES-EST is checked ata set schedule (every 6 months or once a year) or when a patient startsreporting tLESR symptoms using manometry and the patient-specific LESESTparameters are then modified to achieve ideal LES pressure.

It should be appreciated that the aforementioned diagnostic processesaccount for a plurality of variables that substantially affect treatmentquality, treatment efficacy, and patient compliance, including, but notlimited to, patient's disease condition and the correspondingstimulation energy level and frequency required to achieve a positivetherapeutic effect, patient willingness to manually apply stimulation,and form factor of the stimulation source, among other variables.

The variables generated in the course of the diagnostic processes can beused to automatically program a controller, which may be used to controla stimulator. In one embodiment, a diagnostic terminal executing on aconventional computer generates at least one variable, such asstimulation pulse width, frequency, amplitude, ramp rate, or a dutycycle, that substantially affects treatment quality, treatment efficacy,and patient compliance, including, but not limited to, patient's diseasecondition and the corresponding stimulation energy level and frequencyrequired to achieve a positive therapeutic effect, patient willingnessto manually apply stimulation, and form factor of the stimulationsource, among other variables. The diagnostic terminal is in datacommunication with a controller configuration terminal thatelectronically receives a controller into an interface or wirelesslycommunicates with the controller that is responsible for executing thestimulation parameters. Upon generating the variables, the diagnosticterminal transmits the variables, which are eventually received by thecontroller and saved in an appropriate memory location. The controllerthen uses the variables to control one or more stimulation settings.

In another embodiment, the stimulation parameters are checked by aphysician using a data terminal, such as a laptop, tablet computer,mobile device, or personal computer. As discussed above, data relevantto the efficacy of the stimulation parameters can be wirelessly obtainedfrom the stimulation device memory or from a patient controlledcomputing device, such as a tablet computer, laptop, personal computer,or mobile device. The physician can modify the stimulation parameters inaccordance with the received data and, using the data terminal, issuemodified stimulation parameters to the controller of a stimulator asdescribed above.

Exemplary Therapies

The following description is intended to provide examples of how thetherapies, described above, may be specifically implemented. They shouldnot be viewed as limiting the general scope of the inventions describedherein.

Therapy One: Patient Timed and Delivered Stimulation Using a HandheldDevice

In a first therapy, a patient can be effectively therapeutically treatedwith intermittent wireless short bursts of stimulation applied aplurality of times during a day. For example, in one embodiment, apatient can be treated by applying a burst of stimulation for a periodof five minutes or less at a frequency of 5 times or less per day. Inanother embodiment, the stimulation occurs less than 5 times a day for aperiod of 30 minutes or less per stimulation. This stimulation frequencyis effective to treat certain symptoms of a patient, includingdiminishing or eliminating a patient's heartburn, regurgitation or both.

In this treatment method, a patient can be effectively treated by havingthe patient apply an external power source over a predefined area on thepatient's body and manually initiate a stimulation. FIG. 16 is a firstembodiment of a block diagram of certain modules of the presentinvention. In one embodiment, the stimulation system comprises astimulation source 1600 and a microstimulator 1601. As shown in FIG. 16,the stimulation source 1600 comprises a controller 1602, transducer1603, waveform generator 1604, and power source 1605, such as a battery.The stimulation source 1600 directs energy, such as ultrasound or RFenergy, across the patient's skin 1610 and toward a microstimulator 1601that is implanted directly on the site being stimulated. The stimulationsource 1600 can generate a plurality of different pulse widths,amplitudes, frequencies, or combinations thereof, as further describedbelow.

In certain situations, the device may require an energy supply to powerthe implantable pulse generator, but it is difficult or undesirable toinclude an implantable battery that would be wired to the device due tosize limitations, restrictions arising from the implant location, or theneed to decrease device costs. In one embodiment, a rechargeable batteryis wired to the stimulator. The rechargeable battery stores a smalleramount of charge, and therefore can be small in size, but is configuredor adapted to be replenished using wireless transmission of energy.

In another embodiment that requires an implanted device size which iseven smaller than that which is possible with a rechargeable battery andassociated recharging circuit, the device comprises a passive circuitthat receives, in real time, transmitted wireless energy from atransmission source external to the patient. The implanted passivecircuit would control the extraction of the transmitted energy and thedelivery of the energy to the rest of the stimulator device. Theexternal energy transmission device would control the timing ofstimulation and any sensing and/or triggering mechanisms relatedthereto. One limitation to the wireless transmission of energy is theamount of energy that can be wirelessly transmitted in any given timedue, for example, to safety or interference requirements. Such wirelessenergy transmission limitations narrow the applicable stimulationamplitude and waveform that can be applied to the tissue, therebylimiting the clinical application and benefit of such systems.

In another embodiment, the microstimulator comprises a means for storinga charge locally, such as a short-term energy storage component or acapacitor, and an associated trigger mechanism. During an on-off dutycycle for stimulating the microstimulator, the off-time of thestimulation duty cycle can be used to temporarily store a charge,thereby enhancing the maximal amplitude and variety of waveform that canbe applied. The implanted device circuit is configured to control andtime the stimulation in response to energy or control information from acontroller that is external to the patient and communicates wirelesslywith the implanted device. The implanted circuit extracts thetransmitted energy or control information and, in response thereto,shapes the waveform within the off-time of each stimulation cycle usingcomponents such as capacitors, diodes, inductors, transistors andresistors.

The operating characteristics of a capacitor integrated with, or localto, the implanted device will be determined, at least in part, by therequired pulse duration and the ratio of required stimulation pulseamplitude to minimal expected extracted supply current within theimplantable device. The capacitor characteristics will also be afunction of the load impedance. For example, assuming a required pulseduration of 200 μs to be applied every 50 ms and a required amplitude of10 mAmp, the device will need to provide a charge of 2 μC (10 mAmp×200μs). Assuming an impedance of 100 ohms with a voltage of 1 V (10mAmp×100 ohm), then the minimum required capacitor will have a value asapproximated by the following equation:C=Q/V=2 uC/1V=2 uF

This value will need to be adjusted so that it is not fully dischargedduring stimulation and to compensate for losses within the implantabledevice. For an overall cycle of, for example, 50 ms the theoreticalminimal extracted supply current that can drive the required pulse willbe:Minimal extracted current=10 mAmp×200 μs/(50 ms−200 μs)=0.04 mAmp

Adjusting for internal losses within the stimulator will yield apractical limit of about 0.1 mAmp or 100 μAmp. Higher available supplycurrents can allow for shorter cycles or longer pulse duration asnecessary and can be extrapolated from the above.

In one embodiment, energy need not be stored between cycles and thepassive circuit responds, in real-time, to the wireless transmission ofenergy. For example, the implanted circuit may initiate a stimulationpulse in response to a stimulation pulse wirelessly sent by the externalenergy transmitting unit, where the energy transmission is above apre-defined time period, is characterized by the intermittent ceasing ofenergy transmission, or is characterized by another combination of“on”-“off” energy signals.

In one embodiment, the stimulation source 1600 directs ultrasonic energyto the microstimulator 1601 which comprises an ultrasonic receiver. Themicrostimulator 1601 is implanted into the area to be stimulated via anendoscope. The microstimulator 1601 can function either as apass-through for energy and stimulation parameters or comprise an energystorage and programmatic memory to deliver short stimulation bursts,using the stored energy, at predetermined time intervals, pursuant tothe programmed memory.

In one embodiment, the stimulation source 1600 directs radio frequency(RF) energy to the microstimulator 1601 which comprises an RF receiver.The microstimulator 1601 is implanted into the area to be stimulated viaan endoscope. The microstimulator 1601 can function either as apass-through for energy and stimulation parameters or comprise an energystorage and programmatic memory to deliver short stimulation bursts,using the stored energy, at predetermined time intervals, pursuant tothe programmed memory.

In one embodiment, the stimulation source 1600 comprises a controller1602, transducer 1603, waveform generator 1604, and power source 1605,such as a battery. Operationally, the controller 1602, via a processorin data communication with a memory storing programmatic instructions,causes the waveform generator 1604 to generate a predefined waveform,having an associated pulse width, amplitude, and frequency, which istransmitted via the transducer 1603 to the endoscopically implantedmicrostimulator 1601. A patient applies the stimulation source 1600intermittently for a short time period, preferably 30 minutes or less,over the microstimulator 1601 site. Where the microstimulator 1601comprises a local memory for storing programmatic instructions, inparticular stimulation parameters and processes, the stimulation source1600 need not comprise a controller and memory for storing suchprogrammatic instructions and may simply transmit a predefined amount ofenergy to the microstimulator.

In another embodiment, referring to FIG. 17, the stimulation source 1700comprises a controller 1702, waveform generator 1704, and power source1705, such as a battery. It wirelessly communicates with, and/ortransfers energy to, a transducer 1703 that is implanted subcutaneously.The subcutaneous transducer 1703 receives the wirelessly transmittedenergy, such as RF or ultrasound, through the patient's skin surface andtransmits it, via a wired or wireless connection, to an endoscopicallyimplanted microstimulator 1701. Operationally, the controller 1702, viaa processor in data communication with a memory storing programmaticinstructions, causes the waveform generator 1704 to generate apredefined waveform, having an associated pulse width, amplitude, andfrequency, which is transmitted wirelessly into the patient'ssubcutaneous region and into the transducer 1703, which furthertransmits the energy to the microstimulator 1701. A patient applies thestimulation source 1700 intermittently for a short time period,preferably thirty minutes or less, over the transducer site. Where themicrostimulator 1701 comprises a local memory for storing programmaticinstructions, in particular stimulation parameters and processes, thestimulation source 1700 need not comprise a controller and memory forstoring such programmatic instructions and may simply transmit apredefined amount of energy to the transducer 1703 and, thus, to themicrostimulator 1701. It should be appreciated that, regardless of thetype, the stimulation source 1700 can be integrated into a plurality ofdifferent housings, including a miniature flashlight, cell phone case,or smart card. In one embodiment, the subcutaneous transducer 1703receives lower frequency electromagnetic energy and commands from thestimulation source 1700 and converts the energy into high frequency RFenergy. The frequency conversion will be less efficient than direct RFtransmission but the use of the subcutaneous transducer will assist ineliminating heating issues. In addition, the subcutaneous transducer canalso be used as a simple energy storage unit. In another embodiment, thesubcutaneous transducer 1703 receives lower frequency electromagneticenergy and commands from the stimulation source 1700 and converts theenergy into ultrasound energy.

In another embodiment, referring to FIG. 18, a patient is treated bylaparoscopically implanting a plurality of electrodes or electrodes 1801(within the anatomical area to be stimulated) in wired communicationwith a transducer 1803 (comprising an antenna) proximate to the skinsurface. The transducer 1803 wirelessly communicates with an externalenergy source 1800 (comprising a controller 1802, waveform generator1804, and power source 1805, such as a battery) across the surface ofthe patient's skin 1810. The external energy source 1800 can be appliedto the stimulation site by a patient, as described above. With closeenergy source application, radio frequency, ultrasound, orinductive/magnetic energies can be used.

As further discussed below, the stimulation source 1600, 1700, 1800 caninitiate or terminate stimulation, when properly placed over theappropriate site, based on any of a plurality of triggers, includingmanually by a patient, patient activity, or other sensed patient states.The stimulation source 1600, 1700, 1800 can generate a plurality ofdifferent pulse widths, amplitudes, frequencies, or combinationsthereof, as further described below.

Therapy Two: Controller Timed and Delivered Stimulation

In a second therapy, a patient may not be effectively therapeuticallytreated with intermittent wireless short bursts of stimulation applied aplurality of times during a day. Rather, a patient requires bursts ofstimulation for a period greater than a predefined period of time, orfor a frequency of more than a predefined number of times per day.Accordingly, a patient is subjected to stimulation that is initiated,effectuated, or otherwise triggered by a programmed controller. Thismore frequent, or continuous, stimulation is effective to treat certainsymptoms of a patient, including treatment of heartburn orregurgitation, or reaching a predetermined LES pressure, muscle tensionor electrode impedance.

In this treatment method, a patient can be effectively treated by aplurality of embodiments, including:

1) Referring to FIG. 19, endoscopically implanting a microstimulator1901 (having a receiver and placed within the anatomical area to bestimulated) in wireless or wired communication with a subcutaneouslyimplanted transducer 1903 that, in turn, wirelessly communicates with atransducer 1906 (comprising at least one antenna and an adhesivesurface) applied to the patient's skin surface 1910 which is wired to,and receives signals from, a stimulator source 1900 (comprising acontroller 1902, waveform generator 1904, and power source 1905, such asa battery). The controller 1902 can be programmed to initiate orterminate stimulation based on a plurality of patient-specific triggers,such as pH level, LES pressure, fasting state, eating state, sleepingstate, physical incline, or patient activity state, among other triggersas further described below. The stimulation source 1900 can generate andtransmit radio frequency or ultrasound energy and can generate aplurality of different pulse widths, amplitudes, frequencies, orcombinations thereof, as further described below. In one embodiment, theradio frequency or ultrasound pulse is designed to operate over awireless distance of 6 inches or less, through the human body, with amaximum pulse amplitude of 10 mAmp and a maximum pulse width of 10 msec.It should be appreciated that if one parameter is lowered, such as thewireless distance (lowering it to one inch), another parameter can bemodified accordingly, such as the amplitude (increasing it to 30 mAmp).

2) Referring to FIG. 20, endoscopically implanting a microstimulator2001 (having a receiver and placed within the anatomical area to bestimulated) in wireless communication with a stimulator source 2000(comprising a controller 2002, transducer 2003, waveform generator 2004,and power source 2005, such as a battery and which is held against apatient's skin 2010 over the microstimulator site, such as with straps,adhesives, garments, or bindings). The controller 2002 can be programmedto initiate or terminate stimulation based on a plurality ofpatient-specific triggers, such as pH level, LES pressure, fastingstate, eating state, sleeping state, physical incline, or patientactivity state, among other triggers as further described below. Thestimulation source 2000 can generate and transmit radio frequency orultrasound energy and can generate a plurality of different pulsewidths, amplitudes, frequencies, or combinations thereof, as furtherdescribed below. In one embodiment, the radio frequency or ultrasoundpulse is designed to operate over a wireless distance of 6 inches orless, through the human body, with a maximum pulse amplitude of 10 mAmpand a maximum pulse width of 10 msec. It should be appreciated that ifone parameter is lowered, such as the wireless distance (lowering it toone inch), another parameter can be modified accordingly, such as theamplitude (increasing it to 30 mAmp).

3) Referring to FIG. 21, endoscopically implanting a microstimulator2101 (having a receiver and placed within the anatomical area to bestimulated) in wireless communication with a relay device 2106 worn overthe stimulation site 2110 that is in wired communication with anexternal stimulator 2100, in wireless communication with an implantedadapter 2107 that is in wireless communication with an externalstimulator 2100, or in wireless communication with an implantedtransducer 2108 that is in wired communication, via an electrode, to animplanted stimulator 2109. The stimulator 2100 (comprising a controller2102, transducer 2103, waveform generator 2104, and power source 2105,such as a battery) can be programmed to initiate or terminatestimulation based on a plurality of patient-specific triggers, such aspH level, LES pressure, fasting state, eating state, sleeping state,physical incline, or patient activity state, among other triggers asfurther described below. The stimulation source 2100 can generate andtransmit radio frequency or ultrasound energy and can generate aplurality of different pulse widths, amplitudes, frequencies, orcombinations thereof, as further described below. In one embodiment, theradio frequency or ultrasound pulse is designed to operate over awireless distance of 6 inches or less, through the human body, with amaximum pulse amplitude of 10 mA and a maximum pulse width of 10 msec.It should be appreciated that if one parameter is lowered, such as thewireless distance (lowering it to one inch), another parameter can bemodified accordingly, such as the amplitude (increasing it to 30 mAmp).

4) Referring to FIG. 22, laparoscopically implanting a plurality ofelectrodes 2201 (within the anatomical area to be stimulated) in wiredcommunication with an implanted stimulator 2200 (comprising a primarycell that provides energy and a memory with programmatic instructionsfor defining appropriate stimulation parameters) which can be programmedto generate stimulation either continuously or periodically based on apredefined program or based on patient-specific triggers, such as pHlevel, LES pressure, LES impedance, fasting state, eating state,sleeping state, physical incline, or patient activity state, among othertriggers as further described below. The stimulator 2200 may alsowirelessly receive control data or information from an external device,which may be controlled, at least in part, by a physician or patient.The stimulator 2200 can generate a plurality of different pulse widths,amplitudes, frequencies, or combinations thereof, described above.

5) Referring to FIG. 23, laparoscopically implanting a plurality ofelectrodes 2301 (within the anatomical area to be stimulated) in wiredcommunication with a subcutaneously implanted transducer 2302 that, inturn, wirelessly communicates with a stimulator source or a transducer2303 (comprising at least one antenna and an adhesive surface) appliedto the patient's skin surface 2310 which is wired to, and receivessignals from, a stimulator source 2300 (comprising a controller 2304,waveform generator 2305, and power source 2306, such as a battery). Thecontroller 2304 can be programmed to initiate or terminate stimulationbased on a plurality of patient-specific triggers, such as pH level, LESpressure, fasting state, eating state, sleeping state, physical incline,or patient activity state, among other triggers as further describedbelow. The stimulation source 2300 can generate and transmit radiofrequency or ultrasound energy and can generate a plurality of differentpulse widths, amplitudes, frequencies, or combinations thereof, asfurther described below.

It should be appreciated that, while the disclosed system can use RF,inductive coupling, magnetic coupling or ultrasound, in one embodiment,the system can combine the use of RF inductive coupling, magneticcoupling, and ultrasound to take best advantage of transmissionefficiencies in various media. In one embodiment, the externalstimulator source generates RF waveforms, which wirelessly transmits RFenergy to an intermediary receiver, that can be implanted subcutaneouslyand that converts the received RF energy into an ultrasound waveform.The intermediary receiver has an RF receiver, an ultrasound waveformgenerator, and an ultrasound transmitter. In another embodiment, thedevice comprises a means for storing a charge locally, such as ashort-term energy storage component, such as a capacitor, and anassociated trigger mechanism, as described above.

It should further be appreciated that the microstimulator (or, where alaparoscopically implanted stimulation electrode and stimulator areused, the stimulator) can locally store energy, be used with RF or US,and rely on an external device for stimulation control and/or energyrecharge. Specifically, the microstimulator can comprise a means forstoring a charge locally, such as a capacitor. It should further beappreciated that the anatomical region to be stimulated, such as theLES, areas within 2 cm of the LES, the esophagus, or the UES, may bestimulated using a plurality of microstimulators or electrodes,including an array of microstimulators or electrodes affixed to a meshor other substrate. It should further be appreciated the microstimulatoror implanted stimulator can store enough energy to function as a backup,or otherwise fill in gaps in energy transfer from an external sourcewhen, for example, wireless transmission coupling is interrupted orinefficient. In another embodiment, the microstimulator or implantedstimulator receives an energy stream from an external stimulator and, inreal-time, forms the requisite waveform based on parameters encoded in awireless control stream or embedded in the energy stream. In anotherembodiment, the microstimulator or implanted stimulator receives apre-formed waveform from an external stimulator.

As discussed above, the endoscopic therapeutic treatments are part ofthe diagnosis process in which a microstimulator is endoscopicallyimplanted and used in combination with an external device for an initialperiod. Data is gathered regarding frequency of stimulation required,amount of energy required, and other factors. A patient then receives alaparoscopically implanted permanent system operating in accordance withthe gathered data.

Exemplary Use No. 1

In one embodiment, patients with diagnosis of GERD responsive to PPI,increase esophageal acid on 24 h pH monitoring off GERD medications,basal LES pressures≧5 mm Hg, hiatal hernia<2 cm and esophagitis≦LA GradeB had a stimulator placed endoscopically in the LES by creating a 3 cmsubmucosal tunnel. The stimulator was secured to the esophagusmuscularis or serosa. Electrical stimulation (EST) was delivered 6-12hours post-implant per following protocols 1) Short-pulse (SP) 200 μsec,20 Hz, 10 mAmp; if no response in LES pressure increase to 15 mAmp; ifincrease in LES pressure decrease to 5 mAmp and 2) Intermediate-pulse(IP) 3 msec, 20 Hz, 5 mAmp for 20 minutes; if no response, increase to10 mAmp. Each session of EST lasted 20 minutes and was followed by awashout period of 20 minutes or time needed for LES pressure to returnto baseline, whichever was longer. High-resolution manometry wasperformed using standard protocol pre-, during and post-stimulation.Symptoms of heartburn, chest pain, abdominal pain and dysphagia pre-,during and post-stimulation were also recorded. Continuous cardiacmonitoring was performed during and after the stimulation to look forany adverse cardiac events associated with EST.

Three patients underwent successful stimulator implantation. One patientwas stimulated using 200 μsec, 20 Hz, 3 mAmp (SP 3) and had asignificant increase in the LES pressure (Baseline=5.7 mm Hg;post-stimulation=42 mm Hg). As shown in FIGS. 24-30, patients had asignificant increase in the LES pressure with all sessions of EST (Table5). There was no effect on swallow induced relaxation and improvement inpost-swallowing LES pressure augmentation with EST. There were noadverse EST related symptoms or any cardiac rhythm abnormalities.

TABLE 5 EST Protocol Median LES pressure (mmHg) Pre- Post- StimulationStimulation Stimulation SP-10 mAmp 8.1 25.3 17.9 SP-5 mAmp 9.7 37.7 17.8IP-5 mAmp 6.5 26.0 29.2

Accordingly, in patients with GERD, EST results in significant increasein LES pressure without affecting patient swallow function or inducingany adverse symptoms or cardiac rhythm disturbances. EST delivered via awired or wireless electrical stimulator offers a novel therapy topatients with GERD.

Exemplary Use No. 2

In one embodiment, a patient with diagnosis of GERD has a baseline LESpressure of 4-6 mmHg and impedance was about 320 ohms. A stimulationhaving a pulse of 200 μs and 5 mAmp was applied. After 15 minutes, asustained LES tone of 25-35 mmHg was observed, which remained high forover 90 minutes after stopping stimulation. After 3 hours, the LESpressure returned to baseline. This patient was than treated using apatient specific stimulation protocol of 200 μs pulse, 5 mAmp amplitude,20 Hz frequency, an ON phase of 20 minutes and an OFF phase of 2 hours.His LES was restored to normal function and his GERD was controlled.

Exemplary Use No. 3

In one embodiment, a patient with diagnosis of GERD has a baseline LESpressure of 4-6 mmHg and impedance was about 320 ohms. A stimulationhaving a pulse of 200 μs and 10 mAmp was applied. After 15 minutes, asustained LES tone of 25-35 mmHg was observed. The patient wasinstructed to engage in a wet swallow. The patient engaged in a wetswallow, while stimulation was being applied, without feeling anysubstantive inhibition of the swallow function. This patient was thentreated using a patient specific stimulation protocol of 200 μs pulse, 5mAmp amplitude, 20 Hz frequency, an ON phase of 20 minutes and an OFFphase of 2 hours. His LES was restored to normal function and his GERDwas controlled. Optionally, a pressure sensor was implanted in the LESand used to terminate the ON phase when a sustained LES pressure ofgreater than 20 mmHg for 5 minutes was achieved and used to terminatethe OFF phase when a sustained LES pressure reaching 10 mmHg or thepatient's baseline, whichever is higher, was achieved.

Exemplary Use No. 4

In one embodiment, patients are subjected to a series of diagnostictests to determine a plurality of therapeutic stimulation parameters andto select stimulation parameters with the lowest average charge which isstill able to elicit a pressure response in the range of at least 15-20mmHg sustained for at least 5 minutes as measured in manometry. Thediagnostic tests include subjecting patients to a series of stimulationsequences, as provided in the table below:

TABLE 6 Stimulation Sequence Settings Electrical Stimulation Pulse PulseSequence # Type Frequency Duration Pulse Amplitude 1 High-Frequency 20Hz 200 μsec 5 mAmp 2 (only if #1 does High-Frequency 20 Hz 200 μsec10-15 mAmp (preferably not reach 20 10 mAmp) mmHg or invoke asufficiently positive response) 3 (only if #2 does Mid-Frequency 20 Hz 3ms 5-15 mAmp (preferably not reach 20 10 mAmp) mmHg or invoke asufficiently positive response) 4 (only if #3 does Mid-Frequency 20 Hz 3ms 5-15 mAmp not reach 20 mmHg or invoke a sufficiently positiveresponse) 5 (only if #4 does Low-frequency 6 cycles/min 375 ms 5 mAmpnot reach 20 mmHg or invoke a sufficiently positive response) 6 (only if#5 does Low-frequency 6 cycles/min 375 ms 5-15 mAmp not reach 20 mmHg)

Each selected stimulation parameter is applied for 5 hours during whichstimulation is turned on until pressure is greater than or equal to 20mmHg for at least 5 minutes (or until the time of duration reaches 60minutes) and then stimulation is turned off until the pressure drops toless than 10 mmHg, or the patient's baseline, whichever is higher.Stimulation is then turned on again until reaching greater than or equalto 20 mmHg again for at least 5 minutes. This on-off process continueswhile the time duration between each on-off cycle is recorded. If thepatient experiences pain or discomfort for any given stimulationsequence, the pulse amplitude is decreased in 1 mAmp increments untilstimulation is tolerable. Once the tolerable setting is established, thestimulation period is re-initiated. Optionally, there is a washoutperiod between sequences to remove any residual effect from theapplication of a prior sequence. That washout period can be equal to onehour or until LES pressure returns to the patient's baseline, whicheveris longer. Optionally, continuous manometry is performed during thepost-stimulation period to assess any delayed effect from a failedsequence or to measure the duration of effect from a successfulsequence.

During the last two hours of the diagnostic session, stimulation isturned “on” and “off” at fixed durations based on the measured valuesrecorded in the first part of the test. Impedance measurements areperformed periodically during this phase using an external impedancemeasurement device or by measuring the resulting voltage waveform fromstimulation using a floating oscilloscope.

Optionally, a second dosing evaluation process is performed building onthe sequence results as performed above. In one embodiment, a patient'sbaseline LES pressure is evaluated over a 20 minute period. Simulationis applied for 125% of the on time period, as determined from the firstset of sequence measurements. Stimulation is then stopped for 75% of theoff time period, as determined from the first set of sequencemeasurements, or until LES pressure falls below 10 mmHg or baseline,whichever is higher. Restart stimulation for 125% of the on time periodand monitor LES pressure. If LES pressure does not reach 20 mmHg, thencontinue stimulation for up to 150% of the on time period or untilpressure reaches 20 mmHg (whichever comes first). Repeat the off timeperiod and continue cycling between the prior on time period and offtime period until achieving 6 hours of LES pressure above 10 mmHg.Conduct esophageal manometry with wet swallows post stimulationsequence.

Exemplary Use No. 5

In one embodiment, patients are subjected to a series of diagnostictests to determine a plurality of therapeutic stimulation parameters andto select stimulation parameters with the lowest average charge which isstill able to elicit a pressure response in the range of at least 15-20mmHg sustained for at least 5 minutes as measured in manometry. Thediagnostic tests include subjecting patients to a series of stimulationsequences, as provided in the table below:

TABLE 7 Electrical Stimulation Pulse Pulse Pulse Stimulation Sequence #Type Frequency Duration Amplitude Duration 1 Baseline  0 Hz  0 μsec  0mAmp  0 minutes 2 High-Frequency 20 Hz 200 μsec  5 mAmp 30 minutes 3(only if #2 does High-Frequency 20 Hz 200 μsec 10-15 60 minutes notreach 20 mAmp mmHg or invoke a (preferably sufficiently 5 mAmp) positiveresponse) 4 (only if #3 does High-Frequency 20 Hz 200 μsec 10 mAmp 30minutes not reach 20 mmHg or invoke a sufficiently positive response) 5(only if #4 does High-Frequency 20 Hz 200 μsec 5-15 mAmp 60 minutes notreach 20 (preferably mmHg or invoke a 10 mAmp) sufficiently positiveresponse) 6 (only if #5 does High-Frequency 20 Hz 200 μsec 15 mAmp 30minutes not reach 20 mmHg or invoke a sufficiently positive response) 7(only if #6 does High-Frequency 20 Hz 200 μsec 15 mAmp 60 minutes notreach 20 mmHg)

Stimulation is turned on until pressure is greater than or equal to 20mmHg for at least 5 minutes (or until the list time duration is reached)and then stimulation is turned off until the pressure drops to less than10 mmHg, or the patient's baseline, whichever is higher. Stimulation isthen turned on again until reaching greater than or equal to 20 mmHgagain for at least 5 minutes. This on-off process continues while thetime duration between each on-off cycle is recorded. If the patientexperiences pain or discomfort for any given stimulation sequence, thepulse amplitude is decreased in 1 mAmp increments until stimulation istolerable. Once the tolerable setting is established, the stimulationperiod is re-initiated.

Optionally, there is a washout period between sequences to remove anyresidual effect from the application of a prior sequence. That washoutperiod can be equal to one hour or until LES pressure returns to thepatient's baseline, whichever is longer. Optionally, continuousmanometry is performed during the post-stimulation period to assess anydelayed effect from a failed sequence or to measure the duration ofeffect from a successful sequence. Optionally, continuous manometry isperformed during the post-stimulation period from the successfulsequence to determine the duration of the effect, that is, until the LESpressure is below 10 mm Hg or reaches baseline, whichever is higher.

The stimulation sequences listed above may be repeated, if no success isachieved, except using a 3 msec dose instead of the 200 μsec dose.

Optionally, a second dosing evaluation process is performed building onthe sequence results as performed above. In one embodiment, a patient'sbaseline LES pressure is evaluated over a 20 minute period. Simulationis applied for 125% of the on time period, as determined from the firstset of sequence measurements. Stimulation is then stopped for 75% of theoff time period, as determined from the first set of sequencemeasurements, or until LES pressure falls below 10 mmHg or baseline,whichever is higher. Stimulation is restarted for 125% of the on timeperiod and LES pressure is monitored. If LES pressure does not reach 20mmHg, then continue stimulation for up to 150% of the on time period oruntil pressure reaches 20 mmHg (whichever comes first). Repeat the offtime period and continue cycling between the prior on time period andoff time period until achieving 6 hours of LES pressure above 10 mmHg.Conduct esophageal manometry with wet swallows post stimulationsequence. Additional stimulation measurements can be made, includingbaseline manometry with wet swallows, repeating successful sequences foran extended period, such as 12 hours, or manometry measurements with wetswallows after conducting a successful stimulation sequence.

Exemplary Use No. 6

In one embodiment, 10 patients (9 females, 1 male mean age 52.6 years,range-40-60 years) with symptoms of GERD responsive to PPI's, lowresting LES pressure and abnormal 24-hr intraesophageal pH test wereenrolled. All had symptoms of heartburn and/or regurgitation for atleast 3 months, which was responsive to therapy with proton pumpinhibitors (PPI's). Preoperative evaluation included an upper GIendoscopy, esophageal manometry and ambulatory 24-hr esophageal pHrecording. To be included, the patient's resting LESP had to be 5-15mmHg, and the intraesophageal pH had to be less than four more than 5%of the time. Patients with hiatal hernia>3 cm, erosive esophagitis moresevere than Los Angeles grade C, Barretts esophagus or non-GERD relatedesophageal disease were excluded.

Bipolar stitch electrodes were placed longitudinally in the LES duringan elective laparoscopic surgery, secured by a clip and exteriorizedthrough the abdominal wall. It consisted of two platinum-iridiumelectrodes with an exposed length of 10 mm. They were implantedlongitudinally in the right and left lateral aspects the LES and securedby a clip. The electrode was then exteriorized through the laparoscopicport in the abdominal wall in the left upper quadrant and connected to amacro stimulator.

Following recovery, an external pulse generator delivered 2 types ofstimulation for periods of 30 minutes: 1) low energy stimulation; pulsewidth of 200 μsec, frequency of 20 Hz amplitude and current of 5 to 15mA (current was increased up to 15 mA if LESP was less than 15 mmHg),and 2) high energy stimulation; pulse width of 375 msec, frequency of 6cpm and amplitude 5 mA. Resting LESP, amplitude of esophagealcontractions and residual LESP in response to swallows were assessedbefore and after stimulation. Symptoms of chest pain, abdominal pain anddysphagia were recorded before, during and after stimulation and 7-daysafter stimulation. Continuous cardiac monitoring was performed duringand after stimulation.

The high frequency, low energy stimulation was delivered as square-wavepulses with a width of 200 microseconds at a frequency of 20 Hz and acurrent of 5-15 mA. If LESP did not increase to over 15 mmHg using the 5mA stimulus, the current was gradually increased up to 15 mA. The lowfrequency, high energy stimulation was delivered as square-wave pulsewith a width of 375 milliseconds at a frequency of 6 CPM and current of5 mA. The current was not varied during low frequency stimulation.

If resting LESP rose above 15 mmHg during ES, the stimulus wasterminated and LESP was allowed to return to its pre-stimulationbaseline. A different stimulation was given when LESP returned tobaseline. Stimulations were given in random order, with patients unawareof the type or timing of its delivery (frequent checks of impedance weremixed with stimulation). Five water swallows were given before and aftertermination of each session of ES. All studies were done undercontinuous cardiac monitoring, and patients were supervised closely.Patients were instructed to report any unusual symptom, and inparticular dysphagia, palpitations, and chest/abdominal pain.

Nine subjects received high frequency, low energy and four subjectsreceived low frequency, high energy stimulation. Both types ofstimulation significantly increased resting LESP: from 8.6 mmHg 95%, CI4.1-13.1 to 16.6 mmHg, 95% CI 10.8-19.2, p<0.001 with low energystimulation and from 9.2 mmHg 95% CI 2.0-16.3 to 16.5 mmHg, 95% CI2.7-30.1, p=0.03 with high energy stimulation. Neither type ofstimulation affected the amplitude of esophageal peristalsis or residualLESP. No subject complained of dysphagia. One subject had retrosternaldiscomfort with stimulation at 15 mA that was not experienced withstimulation at 13 mA. There were no adverse events or any cardiac rhythmabnormalities with either type of stimulation.

With respect to high frequency, low energy stimulation, there was aconsistent increase in resting LESP in all subjects, observed within 15minutes of initiating ES, and increased further before the end ofstimulation. High frequency, low energy stimulation had no effect on theamplitudes of esophageal contractions or residual LESP in response to 5cc water swallows. One subject had chest discomfort when the stimulationcurrent was increased to 15 mA, but resolved when the current wasdecreases to 13 mA.

With respect to low frequency, high energy stimulation, resting LESPconsistently increased during stimulation. It had no effect on theamplitudes of peristaltic pressure waves in the smooth muscle esophagusor residual LESP produced by 5 cc water swallows. No abnormalities ofcardiac or esophageal function were seen, and no adverse events occurredwith either type of stimulation.

Both types of stimulation, high and low energy stimulation, caused aconsistent and significant increase in LES pressure. Importantly, bothLES relaxation and esophageal contractile activity in response to wetswallows were not affected, indicating that the integrity of theneuromuscular reflex pathways activated by swallows is maintained duringstimulation. Stimulation was well tolerated. No patient reporteddysphagia. Only one patient reported chest discomfort, with amplitude of15 mA, that was not experienced when current was reduced to 13 mA. Therewas no evidence of cardiac adverse effects in any of the patients.Accordingly, short-term stimulation of the LES in patients with GERDsignificantly increases resting LESP without affecting esophagealperistalsis or LES relaxation.

Exemplary Use No 7

Six patients with GERD resistant to medical therapy and documented by pHtesting underwent electrode implantation in the LES using laparoscopy.All patients had LES pressures in the range of 5-15 mm Hg. Amacrostimulator was placed in the subcutaneous pocket using steriletechniques. Within 24 hours after the implant, LES electricalstimulation therapy was started using 215 μsec pulse at 3 mAmp and 20Hz. For certain patients, the macrostimulator comprised anaccelerometer/inclinometer which was used to program the delivery ofstimulation twice daily, once every 12 hours, and then increased to 3times daily, once every 8 hours.

The LES electrical stimulation therapy resulted in significantimprovement and normalization of LES pressure as measured byhigh-resolution manometry and clinically significant decreases inesophageal acid as measured by 24 hour pH testing. All patients haddecreases in symptoms measured by patient symptom diaries andimprovements in health related quality of life measured by a HealthRelated Quality of Life survey, short form 12 (GERD HRQL). All patientswere successfully taken off proton pump inhibitors medications, nor didthe patients use the PPIs on an as-needed basis. None of the patientshad treatment related symptoms or adverse events. All patientsmaintained a normal swallow function.

Referring to FIGS. 24 to 28, the treatment methodologies disclosedherein provide for a sustained improvement in patient LES pressure, adecrease in esophageal acid exposure, and decrease in reported symptoms.Relative to a baseline pressure 2410, patient LES pressure can achieve agreater than 2× increase during stimulation 2415 relative to baseline2410 and can still retain an elevated pressure, relative to baseline2410, after stimulation is terminated 2420.

Additionally, as shown in FIG. 25, a patient's LES pressure can bereliably maintained 2515 within a normal pressure range, 15-25 mmHg, forweeks 2505 after LES stimulation is initiated. As a result, a patient'sesophageal acid exposure 2615 can be brought within a normal pH rangewithin one week after initiating treatment and maintained for severalweeks thereafter 2605. Similarly, a patient's adverse symptoms,associated with GERD, 2715 can be brought within a normal range, asmeasured by GERD HRQL evaluations, within one week after initiatingtreatment and maintained for several weeks thereafter 2705. The benefitsof the present therapy can also be obtained within hours afterinitiating and terminating stimulation. As shown in FIG. 28, relative toa pre-stimulation baseline 2820, a patient's LES pressure can bereliably maintained 2815 within a normal pressure range for hours 2805after LES stimulation is terminated 2830.

While there has been illustrated and described what is at presentconsidered to be a preferred embodiment of the present invention, itwill be understood by those skilled in the art that various changes andmodifications may be made, and equivalents may be substituted forelements thereof without departing from the true scope of the invention.In addition, many modifications may be made to adapt a particularsituation or material to the teachings of the invention withoutdeparting from the central scope thereof. Therefore, it is intended thatthis invention not be limited to the particular embodiment disclosed asthe best mode contemplated for carrying out the invention, but that theinvention will include all embodiments falling within the scope of theappended claims.

What is claimed is:
 1. A system for increasing pressure of a patient'slower esophageal sphincter (LES), comprising: at least one electrodeconfigured to contact a region comprising the LES, wherein the regionconsists of tissue within a distance of 3 cm from the LES; a waveformgenerator coupled to the electrodes; and a controller configured toelectrically stimulate the LES to increase an average pressure of theLES above a baseline such that at least one of a frequency of occurrenceor an intensity of acid reflux symptoms in the patient is reduced duringand/or after stimulation by controlling the waveform generator torepeatedly: a) generate and apply an electrical pulse train to the LESthrough the electrodes for a stimulation period, and b) terminate theelectrical pulse train for a rest period, wherein said electrical pulsetrain comprises a pulse width having a range of 30 μsec to 5 msec, apulse amplitude of 2 to 15 mAmp, an on period ranging from 1 second to23 hours, 59 minutes, and 59 seconds, an off period ranging from 1second to 23 hours, 59 minutes, and 59 seconds, a duty cycle rangingfrom 1 to 100% and a pulse frequency defined such that pressure of theLES normalizes after at least five minutes from when stimulation isinitiated.
 2. The system of claim 1, further comprising an accelerometerwherein said system includes a pre-programmed stimulation mode adaptedto automatically stimulate the patient's LES during time periods inwhich the patient is in a supine position as determined by saidaccelerometer, said supine position being defined by a level ofinclination relative to a vertical baseline wherein 0 degrees is avertical position and wherein said level is programmable and has a rangeof 50 to 80 degrees.
 3. The system of claim 2, wherein said automaticstimulation occurs after the patient has been in the supine position fora predetermined period of time and wherein said predetermined period oftime is programmable and has a range of 1 minute to 60 minutes.
 4. Thesystem of claim 3, wherein said automatic stimulation occurs after aminimum percentage of data points occur within said predetermined periodof time and wherein said minimum percentage of data points isprogrammable and has a range of 50 to 90 percent.
 5. The system of claim1 wherein the system does not comprise a sensor to determine when thepatient is swallowing.
 6. A system for normalizing functionality of apatient's lower esophageal sphincter (LES), comprising: at least oneelectrode configured to contact a region comprising the LES, wherein theregion consists of tissue within a distance of 3 cm from the LES; awaveform generator coupled to the electrodes; and a controllerconfigured to control the waveform generator to generate and apply anelectrical pulse train to the LES through the electrodes during astimulation period to produce said normalization of function in the LESduring and/or after the stimulation period, wherein said electricalpulse train comprises a pulse width having a range of 30 μsec to 5 msec,a pulse amplitude of 2 to 15 mAmp, an on period ranging from 1 second to23 hours, 59 minutes, and 59 seconds, an off period ranging from 1second to 23 hours, 59 minutes, and 59 seconds, a duty cycle rangingfrom 1 to 100% and a pulse frequency defined such that swallowing of thepatient is not hindered by said stimulation.
 7. The system of claim 6,further comprising an accelerometer wherein said system includes apre-programmed stimulation mode adapted to automatically stimulate thepatient's LES during time periods in which the patient is in a supineposition as determined by said accelerometer, said supine position beingdefined by a level of inclination relative to a vertical baselinewherein 0 degrees is a vertical position and wherein said level isprogrammable and has a range of 50 to 80 degrees.
 8. The system of claim7, wherein said automatic stimulation occurs after the patient has beenin the supine position for a predetermined period of time and whereinsaid predetermined period of time is programmable and has a range of 1minute to 60 minutes.
 9. The system of claim 8, wherein said automaticstimulation occurs after a minimum percentage of data points occurwithin said predetermined period of time and wherein said minimumpercentage of data points is programmable and has a range of 50 to 90percent.
 10. The system of claim 6 wherein the system does not comprisea sensor to determine when the patient engages in said swallowing.
 11. Asystem for normalizing a function of a patient's lower esophagealsphincter (LES), comprising: at least one electrode configured tocontact a region comprising the LES, wherein the region consists oftissue within a distance of 3 cm from the LES; a waveform generatorcoupled to the electrodes; and a controller configured to control thewaveform generator to generate and apply an electrical pulse train tothe LES through the electrodes to normalize the function of the LES,which reduces at least one of a frequency of occurrence or an intensityof acid reflux symptoms in the patient, wherein said electrical pulsetrain comprises a pulse width having a range of 30 μsec to 5 msec; apulse amplitude of 2 to 15 mAmp; a pulse frequency of 2 to 80 Hz; an onperiod ranging from 1 second to 23 hours, 59 minutes, and 59 seconds; anoff period ranging from 1 second to 23 hours, 59 minutes, and 59seconds; and a duty cycle ranging from 1 to 100% and a pulse frequencydefined such that said function of the LES normalizes after at leastfive minutes from when stimulation is initiated and such that swallowingof the patient is not hindered by said stimulation.
 12. The system ofclaim 11, further comprising an accelerometer wherein said systemincludes a pre-programmed stimulation mode adapted to automaticallystimulate the patient's LES during time periods in which the patient isin a supine position as determined by said accelerometer, said supineposition being defined by a level of inclination relative to a verticalbaseline wherein 0 degrees is a vertical position and wherein said levelis programmable and has a range of 50 to 80 degrees.
 13. The system ofclaim 12, wherein said automatic stimulation occurs after the patienthas been in the supine position for a predetermined period of time andwherein said predetermined period of time is programmable and has arange of 1 minute to 60 minutes.
 14. The system of claim 13, whereinsaid automatic stimulation occurs after a minimum percentage of datapoints occur within said predetermined period of time and wherein saidminimum percentage of data points is programmable and has a range of 50to 90 percent.
 15. The system of claim 11 wherein the system does notcomprise a sensor to determine when the patient engages in saidswallowing.
 16. A system for increasing pressure of a patient's loweresophageal sphincter (LES), comprising: at least one electrodeconfigured to contact a region comprising the LES, wherein the regionconsists of tissue within a distance of 3 cm from the LES; a waveformgenerator coupled to the electrodes; a battery powering the waveformgenerator; and a controller configured to control the waveform generatorto generate and apply an electrical pulse train to the LES through theelectrodes to increase an average pressure of the LES, the electricalpulse train being controlled by the controller so that an amount ofelectrical energy consumed from the battery when stimulating the LES isan energy amount that increases said average pressure of the LES above abaseline such that at least one of a frequency of occurrence or anintensity of acid reflux symptoms in the patient is reduced whilemaintaining at least a minimum charge on the battery to electricallypower the waveform generator for a predetermined time period, whereinsaid electrical pulse train comprises a pulse width having a range of 30μsec to 5 msec; a pulse amplitude of 2 to 15 mAmp; a pulse frequency of2 to 80 Hz; an on period ranging from 1 second to 23 hours, 59 minutes,and 59 seconds; an off period ranging from 1 second to 23 hours, 59minutes, and 59 seconds; and a duty cycle ranging from 1 to 100% and apulse frequency defined such that the increased pressure level of theLES is below a pressure level that prevents the patient from swallowinga bolus.
 17. The system of claim 16, further comprising an accelerometerwherein said system includes a pre-programmed stimulation mode adaptedto automatically stimulate the patient's LES during time periods inwhich the patient is in a supine position as determined by saidaccelerometer, said supine position being defined by a level ofinclination relative to a vertical baseline wherein 0 degrees is avertical position and wherein said level is programmable and has a rangeof 50 to 80 degrees.
 18. The system of claim 17, wherein said automaticstimulation occurs after the patient has been in the supine position fora predetermined period of time and wherein said predetermined period oftime is programmable and has a range of 1 minute to 60 minutes.
 19. Thesystem of claim 18, wherein said automatic stimulation occurs after aminimum percentage of data points occur within said predetermined periodof time and wherein said minimum percentage of data points isprogrammable and has a range of 50 to 90 percent.
 20. The system ofclaim 16 wherein the system does not comprise a sensor to determine whenthe patient engages in said swallowing.